Use of compounds for the elevation of pyruvate dehydrogenase activity

ABSTRACT

The use of compounds of formula (I), and salts thereof; and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I); and pharmaceutically acceptable salts of said compound or said prodrugs; in formula (I), Ring C is phenyl or a carbon linked heteroaryl ring substituted as defined within; R 1  is an ortho substituent as defined within; n is 1 or 2; A-B is a linking group as defined within; R 2  and R 3  are as defined within; R 4  is hydroxy, hydrogen, halo, amino or methyl; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans is described. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are also described.

[0001] The present invention relates to compounds which elevate pyruvatedehydrogenase (PDH) activity, processes for their preparation,pharmaceutical compositions containing them as active ingredient,methods for the treatment of disease states associated with reduced PDHactivity, to their use as medicaments and to their use in themanufacture of medicaments for use in the elevation of PDH activity inwarm-blooded animals such as humans.

[0002] Within tissues adenosine triphosphate (ATP) provides the energyfor synthesis of complex molecules and, in muscle, for contraction. ATPis generated from the breakdown of energy-rich substrates such asglucose or long chain free fatty acids. In oxidative tissues such asmuscle the majority of the ATP is generated from acetyl CoA which entersthe citric acid cycle, thus the supply of acetyl CoA is a criticaldeterminant of ATP production in oxidative tissues. Acetyl CoA isproduced either by β-oxidation of fatty acids or as a result of glucosemetabolism by the glycolytic pathway. The key regulatory enzyme incontrolling the rate of acetyl CoA formation from glucose is PDH whichcatalyses the oxidation of pyruvate to acetyl CoA and carbon dioxidewith concomitant reduction of nicotinamide adenine dinucleotide (NAD) toNADH.

[0003] In disease states such as both non-insulin dependent (NIDDM) andinsulin-dependent diabetes mellitus (IDDM), oxidation of lipids isincreased with a concomitant reduction in utilisation of glucose, whichcontributes to the hyperglycaemia. Reduced glucose utilisation in bothIDDM and NIDDM is associated with a reduction in PDH activity. Inaddition, a further consequence of reduced PDH activity may be that anincrease in pyruvate concentration results in increased availability oflactate as a substrate for hepatic gluconeogenesis. It is reasonable toexpect that increasing the activity of PDH could increase the rate ofglucose oxidation and hence overall glucose utilisation, in addition toreducing hepatic glucose output. Another factor contributing to diabetesmellitus is impaired insulin secretion, which has been shown to beassociated with reduced PDH activity in pancreatic β-cells (in a rodentgenetic model of diabetes mellitus Zhou et al. (1996) Diabetes 45:580-586).

[0004] Oxidation of glucose is capable of yielding more molecules of ATPper mole of oxygen than is oxidation of fatty acids. In conditions whereenergy demand may exceed energy supply, such as myocardial ischaemia,intermittent claudication, cerebral ischaemia and reperfusion, (Zaidanet al., 1998; J. Neurochem. 70: 233-241), shifting the balance ofsubstrate utilisation in favour of glucose metabolism by elevating PDHactivity may be expected to improve the ability to maintain ATP levelsand hence function.

[0005] An agent which is capable of elevating PDH activity may also beexpected to be of benefit in treating conditions where an excess ofcirculating lactic acid is manifest such as in certain cases of sepsis.

[0006] The agent dichloroacetic acid (DCA) which increases the activityof PDH after acute administration in animals, (Vary et al., 1988; Circ.Shock. 24: 3-18), has been shown to have the predicted effects inreducing glycaemia, (Stacpoole et al. 1978; N. Engl. J. Med. 298:526-530), and as a therapy for myocardial ischaemia (Bersin andStacpoole 1997; American Heart Journal, 134: 841-855) and lacticacidaemia, (Stacpoole et al., 1983; N. Engl. J. Med. 309: 390-396).

[0007] PDH is an intramitochondrial multienzyme complex consisting ofmultiple copies of several subunits including three enzyme activitiesE1, E2 and E3, required for the completion of the conversion of pyruvateto acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). E1catalyses the non-reversible removal of CO₂ from pyruvate; E2 formsacetyl CoA and E3 reduces NAD to NADH. Two additional enzyme activitiesare associated with the complex: a specific kinase which is capable ofphosphorylating E1 at three serine residues and a loosely-associatedspecific phosphatase which reverses the phosphorylation. Phosphorylationof a single one of the three serine residues renders the E1 inactive.The proportion of the PDH in its active (dephosphorylated) state isdetermined by a balance between the activity of the kinase andphosphatase. The activity of the kinase may be regulated in vivo by therelative concentrations of metabolic substrates such as NAD/NADH,CoA/acetylCoA and adenine diphosphate (ADP)/ATP as well as by theavailability of pyruvate itself.

[0008] European Patent Publication Nos. 617010 and 524781 describescompounds which are capable of relaxing bladder smooth muscle and whichmay be used in the treatment of urge incontinence. We have found thatthe compounds of the present invention are very good at elevating PDHactivity, a property nowhere disclosed in EP 0617010 and EP 524781.

[0009] The present invention is based on the surprising discovery thatcertain compounds elevate PDH activity, a property of value in thetreatment of disease states associated with disorders of glucoseutilisation such as diabetes mellitus, obesity, (Curto et al., 1997;Int. J. Obes. 21: 1137-1142), and lactic acidaemia. Additionally thecompounds may be expected to have utility in diseases where supply ofenergy-rich substrates to tissues is limiting such as peripheralvascular disease, (including intermittent claudication), cardiac failureand certain cardiac myopathies, muscle weakness, hyperlipidaemias andatherosclerosis (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530).A compound that activates PDH may also be useful in treating Alzheimer'sdisease (AD) (J Neural Transm (1998) 105, 855-870).

[0010] According to one aspect of the present invention there isprovided the use of compounds of the formula (I):

[0011] wherein:

[0012] ring C is as defined in (a) or (b);

[0013] R¹ is as defined in (c) or (d);

[0014] n is 1 or 2;

[0015] R² and R³ are as defined in (e) or (f);

[0016] A-B is as defined in (g) or (h) and

[0017] R⁴ is as defined in (i) or (j)

[0018] wherein

[0019] (a) ring C is phenyl or carbon-linked heteroaryl selected frompyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; wherein said phenyl orheteroaryl is substituted on carbon at one or both positions meta to theposition of A-B attachment or on carbon at the position para to theposition of A-B attachment by P¹ or P² (wherein P¹ and P² are as definedhereinafter), and further, wherein said phenyl or heteroaryl isoptionally substituted on carbon at any remaining meta position(s) orpara position by P¹ or P³, (wherein P¹ and P³ are as definedhereinafter);

[0020] (b) ring C is selected from the following five groups:

[0021] (i) phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl orheteroaryl is unsubstituted except by (R¹)_(n) wherein R¹ and n are asdefined hereinafter;

[0022] (ii) a carbon-linked triazine optionally substituted on a ringcarbon at a position meta or para to A-B attachment by 1 substituentselected from P¹, P², P³ and P⁴, wherein P¹, P², P³ and P⁴ are asdefined hereinafter;

[0023] (iii) a 6-membered carbon-linked heteroaryl group containing 1-3nitrogen atoms wherein one or more ring nitrogen atoms are oxidised toform the N-oxide, which heteroaryl group is optionally substituted atany of the positions meta or para to A-B attachment by 1-3 substituentsselected from P¹, P², P³ and P⁴, wherein P¹, P², P³ and P⁴ are asdefined hereinafter;

[0024] (iv) phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl orheteroaryl is substituted at a position meta or para to A-B attachmentby 1 substituent selected from P³ and P⁴, wherein P³ and P⁴ are asdefined hereinafter; and

[0025] (v) phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl orheteroaryl is substituted at any of the positions meta or para to A-Battachment by 2-3 substituents selected from P¹, P², P³ and P⁴, providedthat if one or more of the substituents is P¹ or P² then at least one ofthe other substituents is P⁴, wherein

[0026] P¹, P², P³ and P⁴ are as defined hereinafter;

[0027] P¹ is cyano, trifluoromethyl, nitro, trifluoromethoxy ortrifluoromethylsulphanyl;

[0028] P² is —Y¹Ar¹, wherein Ar¹ is selected from the group consistingof phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing1-2 heteroatoms selected independently from O, N and S, wherein saidphenyl or heteroaryl ring is optionally substituted at carbon, with 1-4substituents selected from Q¹, wherein Q¹ is as defined hereinafter; andY¹ is selected from —CO—, —SO— and —SO₂—;

[0029] P³ is C₁₋₄alkyl, haloC₂₋₄alkyl, C₁₋₄alkoxy, haloC₂₋₄alkoxy,C₂₋₄alkenyloxy, halo or hydroxy;

[0030] P⁴ is selected from the following eight groups:

[0031] 1) halosulphonyl, cyanosulphanyl;

[0032] 2) —X¹—R⁵ wherein X¹ is a direct bond, —O—, —S—, —SO—, —SO₂—,—OSO₂—, —SO₂O—, —NR⁶—, —N⁺O⁻R⁶—, —CO—, —COO—, —OCO—, —CONR⁷—, —NR⁸CO—,—OCONR⁹—, —CONR¹⁰SO₂—, —NR¹¹SO₂—, —CH₂—, —NR¹²COO—, —CSNR¹³—, —NR¹⁴CS—,—NR¹⁵CSNR¹⁶—, NR¹⁷CONR¹⁸— or —NR¹⁹CONR²⁰SO₂— (wherein R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ eachindependently represents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl may beoptionally substituted by one or more groups selected from hydroxy,amino, halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy orC₁₋₃alkylsulphanyl) and R⁵ is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl which C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionally substitutedwith one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl with theproviso that P⁴ is not trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy;

[0033] 3) —X¹—C₁₋₆alkyl-X²—R²¹ wherein X¹ is as defined hereinbefore, X²is a direct bond, —O—, —S—, —SO—, —SO₂—, —OSO₂—, —SO₂O—, —NR²²—,—N⁺O⁻R²²—,—CO—, —COO—, —OCO—, —CONR²³—, —NR²⁴CO—, —NR²⁵COO—, —SO₂NR²⁶—,—NR²⁷SO₂—, —CH₂—, —SO₂NR²⁸CO—, —OCONR²⁹—, —CSNR³⁰—, —NR³¹CS—,—NR³²CSNR³³—, —NR³⁴CONR³⁵—, —CONR³⁶SO₂—, —NR³⁷CONR³⁸SO₂, —SO₂NR³⁹CONR⁴⁰—or —SO₂NR³⁹CNNR⁴⁰— (wherein R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰,R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹ and R⁴⁰, each independentlyrepresents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be optionallysubstituted by one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R²¹is hydrogen or C₁₋₄alkyl which C₁₋₄alkyl is optionally substituted withone or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl or R²¹ isR⁴¹ wherein R⁴¹ is phenyl or a 4-12 membered heterocyclic moietycontaining 1-4 heteroatoms selected independently from O, N and S whichheterocyclic moiety may be aromatic or non-aromatic and which phenyl orheterocyclic moiety is optionally substituted by 1-6 substituentsselected from Q³ wherein Q³ is as defined hereinafter with the provisothat P⁴ is not C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy or haloC₁₋₄alkoxy;

[0034] 4) —X¹—C₂₋₆alkenyl-X²—R²¹ wherein X¹, X² and R²¹ are as definedhereinbefore with the proviso that P⁴ is not C₂₋₄alkenyloxy;

[0035] 5) —X¹—C₂₋₆alkynyl-X²—R²¹ wherein X¹, X² and R²¹ are as definedhereinbefore;

[0036] 6) —X¹—C₃₋₇cycloalkyl-X²—R²¹ wherein X¹, X² and R²¹ are asdefined hereinbefore;

[0037] 7) —X¹—C₁₋₆alkylC₃₋₇cycloalkyl-X²—R²¹ wherein X¹, X² and R²¹ areas defined hereinbefore; and

[0038] 8) —Y²Ar² wherein Y² is X¹ wherein X¹ is as defined hereinbeforeand Ar² is selected from the following six groups:

[0039] (i) phenyl, a carbon-linked 6-membered heteroaryl ring containing1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ringcontaining 1-2 heteroatoms selected independently from O, N and S,wherein said phenyl or heteroaryl ring is substituted at carbon, with1-4 substituents selected from Q¹ and Q² including at least onesubstituent selected from Q² wherein Q¹ and Q² are as definedhereinafter;

[0040] (ii) a carbon-linked triazine or a carbon-linked 5-memberedheteroaryl ring containing 3-4 heteroatoms selected independently fromO, N and S; wherein said heteroaryl ring is optionally substituted with1-4 substituents selected from Q¹ and Q² wherein Q¹ and Q² are asdefined hereinafter;

[0041] (iii) a 4-12 membered non-aromatic heterocyclic moiety containing1-4 heteroatoms selected independently from O, N and S wherein saidheterocyclic moiety is optionally substituted with 1-6 substituentsselected from Q³ wherein Q³ is as defined hereinafter, with the provisothat if Ar² is a nitrogen linked heterocyclic ring Y² is not —SO₂—;

[0042] (iv) a 5-membered heteroaryl ring containing 1-4 heteroatomsselected independently from O, N and S, which heteroaryl ring containsat least one nitrogen atom substituted by a group selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, benzoyl orphenylsulphonyl and which heteroaryl ring is optionally substituted by1-3 substituents selected from Q³ wherein Q³ is as defined hereinafter;

[0043] (v) a carbon linked 7-12 membered aromatic heterocyclic moietycontaining 1-4 heteroatoms selected independently from O, N and Swherein said heterocyclic moiety is optionally substituted with 1-6substituents selected from Q³ wherein Q³ is as defined hereinafter; and

[0044] (vi) Ar¹ with the proviso that if Ar² has a value Ar¹ then Y² isnot —CO—, —SO— or —SO₂—;

[0045] Q¹ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₂₋₄alkenyloxy, cyano, nitro, halo or trifluoromethylsulphanyl;

[0046] Q² is selected from the following ten groups:

[0047] 1) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised);

[0048] 2) halosulphonyl, cyanosulphanyl;

[0049] 3) —X³—R⁵ wherein X³ is a direct bond. —O—, —S—, —SO—, —SO₂—,—OSO₂—, —SO₂O—, —NR⁴²—, —N⁺O⁻R⁴²—,—CO—, —COO—, —OCO—, —CONR⁴³—,—NR⁴⁴CO—, —NR⁴⁵COO—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂—, —CH₂—, —SO₂NR⁴⁸CO—,—OCONR⁴⁹—, —CSNR⁵⁰—, —NR⁵¹CS—, —NR⁵²CSNR⁵³—, —NR⁵⁴CONR⁵⁵—, —CONR⁵⁶SO₂—,—NR⁵⁷CONR⁵⁸SO₂—, —SO₂NR⁵⁷CNNR⁵⁸— or —SO₂NR⁵⁹CONR⁶⁰— (wherein R⁴², R⁴³,R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷,R⁵⁸, R⁵⁹, and R⁶⁰ each independently represents hydrogen or C₁₋₄alkylwhich C₁₋₄alkyl may be optionally substituted by one or more groupsselected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R⁵ is as defined hereinbefore butwith the proviso that Q² is not trifluoromethylsulphanyl, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy;

[0050] 4) R⁴¹ wherein R⁴¹ is as defined hereinbefore;

[0051] 5) —X³—C₁₋₆alkyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore but with the proviso that Q² is not C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy or haloC₁₋₄alkoxy;

[0052] 6) —X³—C₂₋₆alkenyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore but with the proviso that Q² is C₂₋₄alkenyloxy;

[0053] 7) —X³—C₂₋₆alkynyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore;

[0054] 8) —X³—C₃₋₇cycloalkyl-X²—R²¹ wherein X³, X² and R²¹ are asdefined hereinbefore;

[0055] 9) —X³—C₁₋₆alkylC₃₋₇cycloalkyl-X²—R²¹ wherein X³, X² and R²¹ areas defined hereinbefore; and

[0056] 10) —X³—R⁴¹ wherein R⁴¹ and X³ are as defined hereinbefore;

[0057] Q³ is selected from the following four groups:

[0058] 1) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised);

[0059] 2) cyano, nitro or halo:

[0060] 3) halosulphonyl, cyanosulphanyl; and

[0061] 4) —X⁴—R⁶¹ wherein X⁴ is a direct bond, —O—, —S—, —SO—, —SO₂—,—OSO₂—, —SO₂O—, —NR⁶²—, —N⁺O⁻R⁶²—,—CO—, —COO—, —OCO—, —CONR⁶³—,—NR⁶⁴CO—, —NR⁶⁵COO—, —SO₂NR⁶⁶—, —NR⁶⁷SO₂—, —CH₂—, —SO₂NR⁶⁸CO—,—OCONR⁶⁹—, —CSNR⁷⁰—, —NR⁷¹CS—, —NR⁷²CSNR⁷³—, —NR⁷⁴CONR⁷⁵—, —CONR⁷⁶SO₂—,—NR⁷⁷CONR⁷⁸SO₂—, —SO₂NR⁷⁹CNNR⁸⁰— or —SO₂NR⁷⁹CONR⁸⁰— (wherein R⁶², R⁶³,R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷,R⁷⁸, R⁷⁹ and R⁸⁰ each independently represents hydrogen or C₁₋₄alkylwhich C₁₋₄alkyl may be optionally substituted by one or more groupsselected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R⁶¹ is selected from hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl which C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionally substitutedwith one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl;

[0062] (c) R¹ is linked to ring C at a carbon ortho to the position ofA-B attachment and is selected from the group consisting of C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkenyloxy, cyano, nitro,halo, trifluoromethylsulphanyl and hydroxy;

[0063] (d) R¹ is linked to ring C at a ring carbon atom ortho to theposition of A-B attachment and is selected from the following twogroups:

[0064] 1) —X⁵—R⁸¹ wherein X⁵ is a direct bond, —O—, —S—, —SO—, —SO₂—,—OSO₂—, —SO₂O—, —NR⁸²—, —CO—, —COO—, —OCO—, —CONR⁸³—, —NR⁸⁴CO—,—NR⁸⁵COO—, —SO₂NR⁸⁶—, —NR⁸⁷SO₂—, —CH₂—, —SO₂NR⁸⁸CO—, —OCONR⁸⁹—,—CSNR⁹⁰—, —NR⁹¹CS—, —NR⁹²CSNR⁹³—, —NR⁹⁴CONR⁹⁵—, —CONR⁹⁶SO₂—,—NR⁹⁷CONR⁹⁸SO₂—, —SO₂NR⁹⁹CNNR¹⁰⁰— or —SO₂NR⁹⁹CONR¹⁰⁰— (wherein R⁸², R⁸³,R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹³, R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷,R⁹⁸, R⁹⁹ and R¹⁰⁰ each independently represents hydrogen or C₁₋₄alkylwhich C₁₋₄alkyl may be optionally substituted by one or more groupsselected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R⁸¹ is selected from hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl which C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionally substitutedwith one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl with theproviso that R¹ is not trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; and

[0065] 2) —X⁶—R¹⁰¹ wherein X⁶ is selected from a direct bond, —CO—, —O—,—OCH₂—, —S—, —SO—, —SO₂— and —NR¹⁰²— (wherein R¹⁰² is hydrogen orC₁₋₄alkyl which C₁₋₄alkyl may be optionally substituted by one or moregroups selected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R¹⁰¹ is phenyl which is optionallysubstituted by 1-4 substituents selected from cyano, nitro,trifluoromethylsulphanyl, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₂₋₆alkenyloxy, halo, hydroxy and amino;

[0066] n is 1 or 2;

[0067] (e) either R² and R³ are independently C₁₋₃alkyl optionallysubstituted by from 1 to 2k+1 atoms selected from fluoro and chlorowherein k is the number of carbon atoms in the said C₁₋₃alkyl, providedthat R² and R³ are not both methyl;

[0068] or R² and R³, together with the carbon atom to which they areattached, form a 3-5 membered cycloalkyl ring optionally substituted byfrom 1 to 2m−2 fluorine atoms wherein m is the number of carbon atoms insaid ring;

[0069] (f) R² and R³ are both methyl or one of R² and R³ is hydrogen orhalo and the other is halo or C₁₋₃alkyl optionally substituted by from 1to 2k+1 atoms selected from fluoro and chloro wherein k is the number ofcarbon atoms in the said C₁₋₃alkyl, with the proviso that when either R²or R³ is halo R⁴ is not hydroxy and with the proviso that when either R²or R³ is hydrogen, R⁴ is not hydrogen;

[0070] (g) A-B is selected from —NHCO—, —OCH₂—, —SCH₂—, —NHCH₂—,trans-vinylene, and ethynylene;

[0071] (h) A-B is —NHCS— or —COCH₂—;

[0072] (i) R⁴ is hydroxy;

[0073] (j) R⁴ is hydrogen, halo, amino or methyl;

[0074] but excluding compounds wherein ring C is selected from (a) andR¹ is selected only from (c) and R² and R³ are selected from (e) and A-Bis selected from (g) and R⁴ is selected from (i); and salts thereof;

[0075] and pharmaceutically acceptable in vivo cleavable prodrugs ofsaid compound of formula (I);

[0076] and pharmaceutically acceptable salts of said compound or saidprodrugs;

[0077] in the manufacture of a medicament for use in the elevation ofPDH activity in warm-blooded animals such as humans.

[0078] Advantageously Q¹ is C₁₋₂alkyl, haloC₁₋₂alkyl, C₁₋₂alkoxy, cyanoor halo.

[0079] In one embodiment of the present invention Ar¹ is phenyl or4-pyridyl and is optionally substituted as defined hereinbefore.

[0080] In another embodiment of the present invention Ar¹ is phenyl andis optionally substituted as defined hereinbefore.

[0081] Preferably Y¹ is —SO₂— or —SO—, more preferably —SO₂—.

[0082] Advantageous values for X¹ are a direct bond, —O—, —S—, —SO—,—SO₂—, —NR⁶—, —CO—, —COO—, —OCO—, —CONR⁷—, —NR⁸CO—, —OCONR⁹—,—CONR¹⁰SO₂—, —NR¹¹SO₂—, —CH₂—, —NR¹²COO—, —CSNR¹³—, —NR¹⁴CS—,—NR¹⁵CSNR¹⁶—, NR¹⁷CONR¹⁸— and —NR¹⁹CONR²⁰SO₂— (wherein R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ eachindependently represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0083] Preferred values for X¹ are —O—, —SO—, —SO₂—, —NR⁶—, —COO—,—CONR⁷—, —NR⁸CO—, —NR¹¹SO₂—, —CH₂— and —NR¹²COO— (wherein R⁶, R⁷, R⁸,R¹¹ and R¹² each independently represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl).

[0084] More preferred values of X¹ are —SO— and —SO₂—.

[0085] Advantageously R⁵ is selected from hydrogen, C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₄alkenyl and C₂₋₄alkynyl which C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₄alkenyl or C₂₋₄alkynyl is optionally substituted asdefined hereinbefore.

[0086] Preferably R⁵ is selected from hydrogen, C₁₋₄alkyl andC₃₋₇cycloalkyl, which C₁₋₄alkyl or C₃₋₇cycloalkyl, is optionallysubstituted as defined hereinbefore.

[0087] Advantageous values for X² are —O—, —NR²²—, —S—, —SO— and —SO₂—,(wherein R²² is hydrogen or C₁₋₄alkyl).

[0088] Preferred values for X² are —O—, —NR²²—, —S—, —SO— and —SO₂—(wherein R²² is hydrogen or C₁₋₂alkyl).

[0089] More preferred values for X² are —O— and —NR²²— (wherein R²² ishydrogen or C₁₋₂alkyl).

[0090] Advantageous values for X⁴ are a direct bond, —O—, —S—, —SO—,—SO₂—, —NR⁶²—, —CO—, —COO—, —OCO—, —CONR⁶³—, —NR⁶⁴CO—, —NR⁶⁵COO—,—SO₂NR⁶⁶—, —NR⁶⁷SO₂—, —CH₂—, —SO₂NR⁶⁸CO—, —OCONR⁶⁹—, —CSNR⁷⁰—, —NR⁷¹CS—,—NR⁷²CSNR⁷³—, —NR⁷⁴CONR⁷⁵—, —CONR⁷⁶SO₂—, —NR⁷⁷CONR⁷⁸SO₂— and—SO₂NR⁷⁹CONR⁸⁰— (wherein R⁶², R⁶³, R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰,R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁹ and R⁸⁰ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0091] Preferred values for X⁴ are —O—, —S—, —SO—, —SO₂—, —NR⁶²—, —COO—,—CONR⁶³—, —NR⁶⁴CO— and —NR⁶⁷SO₂— (wherein R⁶², R⁶³, R⁶⁴ and R⁶⁷ eachindependently represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0092] More preferred values for X⁴ are —O—, —S—, —SO— and —SO₂—.

[0093] In another aspect of the invention more preferred values for X⁴are —O—, —S—, —SO—, —CONR⁶³— and —SO₂—.

[0094] Advantageously R⁶¹ is selected from hydrogen, C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₄alkenyl and C₂₋₄alkynyl which C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₄alkenyl or C₂₋₄alkynyl is optionally substituted ashereinbefore defined.

[0095] Preferably R⁶¹ is selected from hydrogen, C₁₋₄alkyl andC₃₋₇cycloalkyl, which C₁₋₄alkyl or C₃₋₇cycloalkyl is optionallysubstituted as hereinbefore defined.

[0096] Advantageously Q³ is selected from the following three groups:

[0097] (i) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised);

[0098] (ii) cyano, nitro or halo; and

[0099] (iii) —X⁴—R⁶¹ wherein X⁴ and R⁶¹ are as defined hereinbefore.

[0100] Advantageously R⁴¹ is phenyl, a 5-6 membered heterocyclicaromatic ring containing 1-4 heteroatoms selected independently from O,N and S or a 5-7 membered heterocyclic non-aromatic moiety containing1-2 heteroatoms selected independently from O, N and S which phenyl,heterocyclic aromatic ring or heterocyclic non-aromatic moiety isoptionally substituted as defined hereinbefore.

[0101] Advantageously R²¹ is hydrogen or C₁₋₄alkyl.

[0102] Advantageously X³ is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR⁴²—, —CO—, —COO—, —OCO—, —CONR⁴³—, —NR⁴⁴CO—, —NR⁴⁵COO—, —SO₂NR⁴⁶—,—NR⁴⁷SO₂—, —CH₂—, —SO₂NR⁴⁸CO—, —OCONR⁴⁹—, —CSNR⁵⁰—, —NR⁵¹CS—,—NR⁵²CSNR⁵³—, —NR⁵⁴CONR⁵⁵—, —CONR⁵⁶SO₂—, —NR⁵⁷CONR⁵⁸SO₂— or—SO₂NR⁵⁹CONR⁶⁰— (wherein R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰,R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹ and R⁶⁰ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0103] Preferably X³ is —O—, —S—, —SO—, —SO₂—, —NR⁴²—, —COO—, —CONR⁴³—,—NR⁴⁴CO—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂—, —SO₂NR⁴⁸CO— or —CONR⁵⁶SO₂— (wherein R⁴²,R⁴³, R⁴⁴, R⁴⁶, R⁴⁷, R⁴⁸ and R⁵⁶ each independently represents hydrogen,C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0104] Advantageously Q² is selected from the following seven groups:

[0105] 1) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised);

[0106] 2) halosulphonyl, cyanosulphanyl;

[0107] 3) —X³—R⁵ wherein X³ and R⁵ are as defined hereinbefore but withthe proviso that Q² is not trifluoromethylsulphanyl, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy;

[0108] 4) R⁴¹ wherein R⁴¹ is as defined hereinbefore;

[0109] 5) —X³—C₁₋₄alkyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore;

[0110] 6) —X³—C₃₋₇cycloalkyl-X²—R²¹ wherein X³, X² and R²¹ are asdefined hereinbefore; and

[0111] 7) —X³—R⁴¹ wherein R⁴¹ and X³ are as defined hereinbefore.

[0112] Preferably Q² is —X³—R⁵ wherein X³ and R⁵ are as definedhereinbefore but with the proviso that Q² is nottrifluoromethylsulphanyl, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy.

[0113] Advantageously Ar² is selected from the following two groups:

[0114] 1) phenyl, a carbon-linked 6-membered heteroaryl ring containing1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ringcontaining 1-2 heteroatoms selected independently from O, N and S,wherein said phenyl or heteroaryl ring is substituted at carbon, with1-4 substituents selected from Q¹ and Q² including at least onesubstituent selected from Q² wherein Q¹ and Q² are as definedhereinafter; and

[0115] 2) Ar¹ with the proviso that if Ar² has a value Ar¹ then Y² isnot —CO—, —SO— or —SO₂—.

[0116] Preferably Ar² is phenyl substituted with one substituentselected from Q².

[0117] Advantageously P⁴ is selected from the following five groups:

[0118] 1) halosulphonyl, cyanosulphanyl;

[0119] 2) —X¹—R⁵ wherein X¹ and R⁵ are as defined hereinbefore with theproviso that P⁴ is not trifluoromethyl, trifluoromethoxy,trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy;

[0120] 3) —X¹—C₁₋₄alkyl-X²—R²¹ wherein X¹, X² and R²¹ are as definedhereinbefore;

[0121] 4) —X¹—C₃₋₇cycloalkyl-X²—R²¹ wherein X¹, X² and R²¹ are asdefined hereinbefore; and

[0122] 5) —Y²Ar² wherein Y² and Ar² are as defined hereinbefore.

[0123] Preferably P⁴ is selected from the following three groups:

[0124] 1) halosulphonyl, cyanosulphanyl;

[0125] 2) —X¹—R⁵ wherein X¹ and R⁵ are as defined hereinbefore with theproviso that P⁴ is not trifluoromethyl, trifluoromethoxy,trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; and

[0126] 3) —Y²A² wherein Y² and Ar² are as defined hereinbefore.

[0127] Advantageously R¹⁰¹ is phenyl which is optionally substituted by1-4 substituents selected from cyano, nitro, trifluoromethylsulphanyl,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkenyloxy,halo, hydroxy and amino.

[0128] Advantageously X⁶ is selected from a direct bond. —CO—, —O—,—OCH₂—, —S—, —SO—, —SO₂— and —NR¹⁰²— (wherein R¹⁰² is hydrogen orC₁₋₂alkyl).

[0129] Advantageously R⁸¹ is selected from hydrogen, C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₄alkenyl and C₂₋₄alkynyl which C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₄alkenyl or C₂₋₄alkynyl is optionally substituted asdefined hereinbefore.

[0130] Preferably R⁸¹ is selected from hydrogen, C₁₋₄alkyl andC₃₋₇cycloalkyl, which C₁₋₄alkyl and C₃₋₇cycloalkyl is optionallysubstituted as defined hereinbefore.

[0131] Advantageously X⁵ is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR⁸²—, —CO—, —COO—, —OCO—, —CONR⁸³—, —NR⁸⁴CO—, —NR⁸⁵COO—, —SO₂NR⁸⁶—,—NR⁸⁷SO₂—, —CH₂—, —SO₂NR⁸⁸CO—, —OCONR⁸⁹—, —CSNR⁹⁰—, —NR⁹¹CS—,—NR⁹²CSNR⁹³—, —NR⁹⁴CONR⁹⁵—, —CONR⁹⁶SO₂— —NR⁹⁷CONR⁹⁸SO₂— or—SO₂NR⁹⁹CONR¹⁰⁰ (wherein R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁹, R⁹⁰,R⁹¹, R⁹², R⁹³, R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷, R⁹⁸, R⁹⁹ and R¹⁰⁰ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0132] Preferably X⁵ is a direct bond. —O—, —NR⁸²—, —CO—, —COO—,—CONR⁸³—, NR⁸⁴CO—, —NR⁸⁷SO₂— (wherein R⁸², R⁸³, R⁸⁴, and R⁸⁷ eachindependently represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

[0133] Advantageous values for R¹ in group (c) are C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, cyano, nitro, halo and hydroxy.

[0134] Preferred values for R¹ in group (c) are C₁₋₂alkyl, C₁₋₂alkoxy,cyano, nitro, halo and hydroxy.

[0135] More preferred values for R¹ in group (c) are methyl, methoxy,nitro, fluoro, chloro, bromo and hydroxy.

[0136] Particular values for R¹ in group (c) are methoxy, nitro, fluoro,chloro, bromo and hydroxy.

[0137] In one aspect of the invention preferably R¹ is selected fromhalo, nitro, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl andhydrogen.

[0138] In another aspect of the invention preferably R¹ is selected fromC₁₋₄alkoxy, halo, nitro or R¹ is X⁵—R⁸¹ wherein X⁵ is a direct bond,—NH—, —NHCO—, —SO—, —SO₂—, —NHSO₂— and R⁸¹ is H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl or R¹ is —X⁶—R¹⁰¹ wherein —X⁶ is —CO— and R¹⁰¹ is phenylsubstituted by halo.

[0139] In a further aspect of the invention preferably R¹ is selectedfrom fluoro and chloro.

[0140] In an additional aspect of the invention, preferably R¹ is nothydrogen.

[0141] Preferably n is 1.

[0142] A preferred value for A-B in group (g) is NHCO.

[0143] Advantageous values for ring C in group (a) are:

[0144] phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl issubstituted as defined hereinbefore.

[0145] More advantageous values for ring C in group (a) are:

[0146] phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl issubstituted on carbon at the position para to the position of A-Battachment by a group selected from cyano, trifluoromethyl, nitro,trifluoromethoxy, trifluoromethylsulphanyl and a group P² (wherein A-Band P² are as defined hereinbefore).

[0147] Preferred values for ring C in group (a) are:

[0148] phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl issubstituted on carbon at the position para to the position of A-Battachment by a group selected from cyano, trifluoromethyl, nitro and agroup P² (wherein A-B and P² are as defined hereinbefore).

[0149] More preferred values for ring C in group (a) are:

[0150] phenyl or carbon-linked pyridyl wherein said phenyl or pyridyl issubstituted on carbon at the position para to the position of A-Battachment by a group P² (wherein A-B and P² are as definedhereinbefore).

[0151] A particular value for ring C in group (a) is phenyl which issubstituted as defined hereinbefore.

[0152] A more particular value for ring C in group (a) is phenyl whichis substituted on carbon at the position para to the position of A-Battachment by a group P² (wherein A-B and P² are as definedhereinbefore).

[0153] Advantageous values for ring C in group (b) are:

[0154] (i) phenyl or pyridyl wherein said phenyl or pyridyl isunsubstituted except by (R¹)_(n) wherein R¹ and n are as definedhereinbefore;

[0155] (ii) a carbon-linked triazine optionally substituted on a ringcarbon at a position para to A-B attachment by 1 substituent selectedfrom P¹, P², P³ and P⁴, wherein A-B, P¹, P², P³ and P⁴ are as definedhereinbefore;

[0156] (iii) a 6-membered carbon-linked heteroaryl group containing 1-3nitrogen atoms wherein one or more ring nitrogen atoms are oxidised toform the N-oxide, which heteroaryl group is optionally substituted at aposition para to A-B attachment by 1 substituent selected from P¹, P²,P³ and P⁴, wherein A-B, P¹, P², P³ and P⁴ are as defined hereinbefore;

[0157] (iv) phenyl or carbon-linked pyridyl wherein said phenyl orpyridyl is substituted at a position para to A-B attachment by 1substituent selected from P³ and P⁴, wherein A-B, P³ and P⁴ are asdefined hereinbefore; and

[0158] (v) phenyl or carbon-linked pyridyl wherein said phenyl orpyridyl is substituted at any of the positions meta or para to A-Battachment by 2-3 substituents selected from P¹, P², P³ and P⁴, providedthat if one or more of the substituents is P¹ or P² then at least one ofthe other substituents is P⁴, wherein A-B, P¹, P², P³ and P⁴ are asdefined hereinbefore.

[0159] More advantageous values for ring C in group (b) are:

[0160] (i) phenyl or pyridyl wherein said phenyl or pyridyl isunsubstituted except by (R¹)_(n) wherein R¹ and n are as definedhereinbefore;

[0161] (ii) a 6-membered carbon-linked heteroaryl group containing 1-3nitrogen atoms wherein one or more ring nitrogen atoms are oxidised toform the N-oxide, which heteroaryl group is optionally substituted at aposition para to A-B attachment by 1 substituent selected from P¹, P²,P³ and P⁴, wherein A-B, P¹, P², P³ and P⁴ are as defined hereinbefore;and

[0162] (iii) phenyl or carbon-linked pyridyl wherein said phenyl orpyridyl is substituted at a position para to A-B attachment by 1substituent selected from P³ and P⁴, wherein A-B, P³ and P⁴ are asdefined hereinbefore.

[0163] Preferred values for ring C in group (b) are:

[0164] (i) phenyl or pyridyl wherein said phenyl or pyridyl isunsubstituted except by (R¹)_(n) wherein R¹ and n are as definedhereinbefore; and

[0165] (ii) phenyl or carbon-linked pyridyl wherein said phenyl orpyridyl is substituted at a position para to A-B attachment by 1substituent selected from P³ and P⁴, wherein A-B, P³ and P⁴ are asdefined hereinbefore.

[0166] More preferred values for ring C in group (b) are:

[0167] (i) phenyl or pyridyl wherein said phenyl or pyridyl isunsubstituted except by (R¹)_(n) wherein R¹ and n are as definedhereinbefore;

[0168] (ii) phenyl or carbon-linked pyridyl wherein said phenyl orpyridyl is substituted at a position para to A-B attachment by —Y²Ar²wherein A-B, Y² and Ar² are as defined hereinbefore.

[0169] A particular value for ring C in group (b) is phenyl wherein saidphenyl is substituted at a position para to A-B attachment by —Y²Ar²wherein A-B, Y² and Ar² are as defined hereinbefore.

[0170] In an further feature of the invention preferably ring C isphenyl substituted by one group selected from P⁴ wherein P⁴ is asdefined above.

[0171] More preferably ring C is phenyl substituted at a position parato A-B by a group selected from:

[0172] 1) —X¹—R⁵ wherein X¹ is a direct bond. —O—, —S—, —SO—, —SO₂—,—NR⁶— or —CONR⁷— (wherein R⁶ and R⁷ each independently representshydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be optionally substituted byone or more groups selected from hydroxy or C₁₋₆alkoxy) and R⁵ isselected from hydrogen and C₁₋₆alkyl, which C₁₋₆alkyl, is optionallysubstituted with one or more groups selected from hydroxy and C₁₋₆alkoxyand hydroxyC₁₋₆alkyl with the proviso that —X¹—R⁵ is not hydroxy,C₁₋₄alkyl or C₁₋₄alkoxy;

[0173] 2) —X¹—C₁₋₆alkyl-X²—R²¹ wherein X¹ is a direct bond, —O—, —S—,—SO—, —SO₂—, —NR⁶— or —CONR⁷— (wherein R⁶ and R⁷ each independentlyrepresents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be optionallysubstituted by one or more groups selected from hydroxy or C₁₋₆alkoxy),X² is a direct bond, —O—, —S—, —SO—, —SO₂—, —NR²²— or —CONR²³— (whereinR²² and R²³ each independently represents hydrogen or C₁₋₄alkyl whichC₁₋₄alkyl may be optionally substituted by one or more groups selectedfrom hydroxy or C₁₋₆alkoxy) and R²¹ is hydrogen or C₁₋₄alkyl, whichC₁₋₄alkyl is optionally substituted with one or more groups selectedfrom hydroxy or C₁₋₆alkoxy or R²¹ is R⁴¹ wherein R⁴¹ is as definedhereinbefore with the proviso that —X¹—C₁₋₆alkyl-X²—R²¹ is not C₁₋₄alkylor C₁₋₄alkoxy;

[0174] 3) —Y²Ar² wherein Y² is X¹ wherein X¹ is a direct bond, —O—, —S—,—SO—, —SO₂—, —NR⁶— or —CONR⁷— (wherein R⁶ and R⁷ each independentlyrepresents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be optionallysubstituted by one or more groups selected from hydroxy or C₁₋₆alkoxy)and Ar² is as defined hereinbefore.

[0175] Advantageously when selected from group (e) R² and R³ areindependently C₁₋₃alkyl optionally substituted by from 1 to 2k+1 atomsselected from fluoro and chloro, wherein k is the number of carbon atomsin the said C₁₋₃alkyl, provided that R² and R³ are not both methyl; or

[0176] R² and R³, together with the carbon atom to which they areattached, form a cyclopropane ring optionally substituted by from 1 to 4fluorine atoms.

[0177] Preferably when selected from group (e) R² and R³ areindependently C₁₋₃alkyl optionally substituted by from 1 to 2k+1fluorine atoms, wherein k is the number of carbon atoms in the saidC₁₋₃alkyl, provided that R² and R³ are not both methyl; or

[0178] R² and R³, together with the carbon atom to which they areattached, form a cyclopropane ring optionally substituted by from 1 to 4fluorine atoms.

[0179] More preferably when selected from group (e) R² and R³ areindependently methyl, fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl and perfluoroethyl provided that R² and R³ are notboth methyl; or

[0180] R² and R³, together with the carbon atom to which they areattached, form a cyclopropane ring optionally substituted by from 1 to 4fluorine atoms.

[0181] Particularly when selected from group (e) R² and R³ areindependently methyl, fluoromethyl, difluoromethyl and trifluoromethyl,provided that R² and R³ are not both methyl; or

[0182] R² and R³. together with the carbon atom to which they areattached, form a cyclopropane ring optionally substituted by from 1 to 4fluorine atoms.

[0183] Advantageously when selected from group (f) R² and R³ are bothmethyl or one of R² and R³ is hydrogen or halo and the other is halo orC₁₋₃alkyl optionally substituted by from 1 to 2k+1 atoms selected fromfluoro and chloro wherein k is the number of carbon atoms in the saidC₁₋₃alkyl, with the proviso that when either R² or R³ is halo R⁴ is nothydroxy and with the proviso that when either R² or R³ is hydrogen, R⁴is not hydrogen.

[0184] More advantageously when selected from group (f) R² and R³ areboth methyl or one of R² and R³ is hydrogen or chloro and the other ischloro or methyl with the proviso that when either R² or R³ is chloro R⁴is not hydroxy and with the proviso that when either R² or R³ ishydrogen, R⁴ is not hydrogen.

[0185] Preferably when selected from group (f) R² and R³ are both methylor both chloro with the proviso that when R² and R³ are both chloro R⁴is not hydroxy.

[0186] More preferably when selected from group (f) R² and R³ are bothmethyl.

[0187] Preferably when selected from group (j) R⁴ is hydrogen.

[0188] Where applicable, the R-configuration generally represents apreferred stereochemistry for compounds of formula (I).

[0189] Preferably R¹ is selected from group (c) as defined hereinbefore.

[0190] Preferably A-B is selected from group (g) as definedhereinbefore.

[0191] Preferably R⁴ is selected from group (i) as defined hereinbefore.

[0192] In another aspect of the invention, preferably R⁴ is hydroxy,hydrogen or methyl.

[0193] Advantageously ring C is selected from the following values fromgroup (a):

[0194] phenyl substituted at the position para to the position of A-Battachment by —Y¹Ar¹ wherein Y¹ is —SO— or —SO₂— and Ar¹ is phenyl or3-pyridyl which phenyl or 3-pyridyl is optionally substituted as definedhereinbefore;

[0195] or from the following values from group (b):

[0196] (i) phenyl unsubstituted except by (R¹)_(n) wherein R¹ and n areas defined hereinbefore; and

[0197] (ii) phenyl substituted at the position para to A-B attachment by1 substituent selected from P³ and P⁴ wherein P³ and P⁴ are as definedhereinbefore.

[0198] More advantageously ring C is selected from the following valuesfrom group (a):

[0199] phenyl substituted at the position para to the position of A-Battachment by —Y¹Ar¹ wherein Y¹ is —SO— or —SO₂— and Ar¹ is phenyl or3-pyridyl which phenyl or 3-pyridyl is optionally substituted as definedhereinbefore;

[0200] or from the following values from group (b):

[0201] (i) phenyl unsubstituted except by (R¹)_(n) wherein R¹ and n areas defined hereinbefore; and

[0202] (ii) phenyl substituted at the position para to A-B attachment by1 substituent selected from halo and P⁴ wherein P⁴ is selected from thethree following groups:

[0203] 1) halosulphonyl, cyanosulphanyl;

[0204] 2) —X¹—R⁵ wherein X¹ and R⁵ are as defined hereinbefore with theproviso that P⁴ is not trifluoromethyl, trifluoromethoxy,trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; and

[0205] 3) —Y²Ar² wherein Y² and Ar² are as defined hereinbefore.

[0206] Preferably ring C is selected from the following values fromgroup (a):

[0207] phenyl substituted at the position para to the position of A-Battachment by —Y¹Ar¹ wherein Y¹ is —SO— or —SO₂— and Ar¹ is phenyl or3-pyridyl which phenyl or 3-pyridyl is optionally substituted as definedhereinbefore;

[0208] or from the following values from group (b):

[0209] (i) phenyl unsubstituted except by (R¹)_(n) wherein R¹ and n areas defined hereinbefore; and

[0210] (ii) phenyl substituted at the position para to A-B attachment by1 substituent selected from halo and P⁴ wherein P⁴ is selected from thethree following groups:

[0211] 1) halosulphonyl;

[0212] 2) —X¹—R⁵ wherein X¹ and R⁵ are as defined hereinbefore with theproviso that P⁴ is not trifluoromethyl, trifluoromethoxy,trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; and

[0213] 3) —Y²Ar² wherein either

[0214] (i) Ar² is phenyl or 3-pyridyl wherein said phenyl or pyridyl issubstituted at carbon with 1-4 substituents selected from Q¹ and Q²including at least one substituent selected from Q² wherein Q¹ and Q²are as defined hereinbefore, and Y² is —S—, —SO—, —SO₂— or —CONR⁷—wherein R⁷ is hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl; or

[0215] (ii) Ar² is phenyl or 3-pyridyl wherein said phenyl or pyridyl issubstituted at carbon with 1-4 substituents selected from Q¹ wherein Q¹is as defined hereinbefore and Y² is —S— or —CONR⁷— wherein R⁷ ishydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl.

[0216] Preferably R² and R³ are selected from the following values fromgroup (e):

[0217] R² and R³ are independently methyl, fluoromethyl, difluoromethyland trifluoromethyl, provided that R² and R³ are not both methyl; or

[0218] R² and R³ are selected from the following values from group (f):

[0219] R² and R³ are both methyl.

[0220] More preferably one of R² and R³ is trifluoromethyl and the otheris methyl or both R² and R³ are methyl.

[0221] In one aspect of the invention preferably R² and R³ areindependently C_(k)alkyl optionally substituted by from 1 to 2k+1 atomsselected from fluoro and chloro wherein k is 1-3,

[0222] or R² and R³ together with the carbon atom to which they areattached, form a 3-membered cycloalkyl ring.

[0223] In another aspect of the invention preferably R² and R³ areindependently C_(k)alkyl optionally substituted by from 1 to 2k+1 atomsselected from fluoro and chloro wherein k is 1-3.

[0224] According to a further aspect of the present invention there areprovided compounds of the formula (I), as defined hereinbefore, andsalts thereof;

[0225] and pharmaceutically acceptable in vivo cleavable prodrugs ofsaid compound of formula (I);

[0226] and pharmaceutically acceptable salts of said compound or saidprodrugs;

[0227] but excluding the following compounds:2-hydroxy-N-(2-methoxyphenyl)-2-methylpropanamide;2-hydroxy-N-(2-methylphenyl)-2-methylpropanamide;2-hydroxy-N-(2-methylphenyl)propanamide;N-(2,4-dimethylphenyl)-2-hydroxypropanamide;N-(2,5-dimethylphenyl)-2-hydroxypropanamide;N-(2,6-dimethylphenyl)-2-hydroxypropanamide;N-(2-chlorophenyl)-2-hydroxypropanamide;2-hydroxy-N-(2-methoxyphenyl)propanamide;N-(2,5-dimethoxyphenyl)-2-hydroxypropanamide;N-(2-ethoxyphenyl)-2-hydroxypropanamide;

[0228] N-(2,5-dimethoxyphenyl)-2-hydroxy-2-methylpropanamide;N-(2-ethoxyphenyl)-2-hydroxy-2-methylpropanamide;3-chloro-N-(2,5-dichlorophenyl)-2-hydroxy-2-methylpropanamide;3-chloro-N-(2,4-dichlorophenyl)-2-hydroxy-2-methylpropanamide;N-(2,3-dichloro-5-nitrophenyl)-2-hydroxy-2-methylpropanamide;2-hydroxy-2-methyl-N-(2,3,4-trichlorophenyl)propanamide;1-(2,5-dihydroxyphenyl)-3-hydroxy-3-methylbut-1-ene;1-(2,4-dichlorophenyl)-3-hydroxy-4,4,4-trifluoro-3-trifluoromethylbut-1-ene;2-hydroxy-N-(5-methoxycarbonyl-2-methylphenyl)-2-methylpropylamine;1-(2,6-dimethoxyphenoxy)-2-isopropylpropan-2-ol;1-(2,6-dimethoxyphenoxy)-2-methylpentan-2-ol;1-(2,6-dimethoxyphenoxy)-2-methylbutan-2-ol;1-(2,5-dimethoxyphenoxy)-2-methylpentan-2-ol;1-(2,4-dimethoxyphenoxy)-2-methylpentan-2-ol;1-(2,3-dimethoxyphenoxy)-2-methylpentan-2-ol;1-(2,6-dimethoxyphenoxy)-2-ethylbutan-2-ol;2-ethyl-1-(2-methylphenoxy)butan-2-ol;1-(2-[2-ethyl-2-hydroxybutoxy]phenoxy)-2-ethylbutan-2-ol;2-ethyl-1-(2-methoxyphenoxy)butan-2-ol;1-(2-methoxyphenoxy)-2-methylbutan-2-ol and2-ethyl-1-(2-methoxyphenoxy)pentan-2-ol; for use as medicaments.

[0229] According to a further aspect of the present invention there areprovided compounds of the formula (I), as defined hereinbefore, with theprovisos that:

[0230] (i) ring C bears a group other than hydrogen at the position parato A-B attachment;

[0231] (ii) when A-B is —COCH₂—, —SCH₂—, —OCH₂—, trans-vinylene orethynylene, ring C does not have an oxygen atom linked at a positionortho to A-B attachment;

[0232] (iii) when A-B is ethynylene, ring C does not have fluorine atomslinked at both of the positions ortho to A-B attachment;

[0233] (iv) when A-B is trans-vinylene, ring C does not bear methylgroups at both of the positions ortho to A-B attachment, and does notbear a formyl group at a position ortho to A-B attachment;

[0234] (v) when A-B is —COCH₂—, ring C does not bear methyl groups atboth of the positions ortho to A-B attachment;

[0235] (vi) when A-B is —OCH₂—, ring C does not have chlorine atomslinked at both of the positions ortho to A-B attachment and does notbear nitro groups at both of the positions ortho to A-B attachment;

[0236] (vii) when A-B is —NHCH₂—, ring C does not bear two nitro groupsat positions ortho and para to A-B attachment and does not bear twomethyl groups at positions meta and para to A-B attachment; and

[0237] (viii) when A-B is —SCH₂—, ring C does not simultaneously bear anamino group at a position ortho to A-B attachment and a nitro group atthe position para to A-B attachment;

[0238] and excluding the following compounds:N-(4-chloro-2-nitrophenyl)-2-hydroxy-2-methylpropanamide;N-(4,5-dichloro-2-(2-hydroxy-2-methylpropanamido)phenyl)-2-hydroxy-2-methylpropanamide;N-(4-chloro-2-benzoylphenyl)-2-hydroxy-2-methylpropanamide;N-(2,4-dimethylphenyl)-2-hydroxypropanamide;3-chloro-N-(2,4-dichlorophenyl)-2-hydroxy-2-methylpropanamide;2-hydroxy-2-methyl-N-(2,3,4-trichlorophenyl)propanamide;1-(2,4-dichlorophenyl)-3-hydroxy-4,4,4-trifluoro-3-trifluoromethylbut-1-ene;1-(4-bromo-2-fluorophenyl)-3-hydroxy-3-methylbut-1-yne;1-(2-fluoro-4-pent-1-enylphenyl)-3-hydroxy-3-methylbut-1-yne;1-(4-[3-hydroxy-3-methylbut-1-yn-1-yl]-2-phenylphenyl)-3-hydroxy-3-methylbut-1-yne;1-(2-fluoro-4-pentoxyphenyl)-3-hydroxy-3-methylbut-1-yne;1-(2-fluoro-4-trifluoromethylphenyl)-3-hydroxy-3-methylbut-1-yne;1-(2,5-dimethyl-4-[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)-3-hydroxy-3-methylbut-1-yne;1-(2,4-di[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)-3-hydroxy-3-methylbut-1-yne;3-hydroxy-3-methyl-1-(2,4,5-tri[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)but-1-yne;3-hydroxy-3-methyl-1-(2,3,4,5-tetra[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)but-1-yneand3-hydroxy-3-methyl-1-(2,3,4,5,6-penta[3-hydroxy-3-methylbut-1-yn-1-yl]phenyl)but-1-yne;and salts thereof;

[0239] and pharmaceutically acceptable in vivo cleavable prodrugs ofsaid compound of formula (I);

[0240] and pharmaceutically acceptable salts of said compound or saidprodrugs.

[0241] According to a further aspect of the present invention there areprovided compounds of the formula (I), as defined hereinbefore, whereinA-B is —NHCO— and with the proviso that ring C bears a group other thanhydrogen at the position para to A-B attachment and excluding thefollowing compounds:N-(4-chloro-2-nitrophenyl)-2-hydroxy-2-methylpropanamide;N-(4,5-dichloro-2-(2-hydroxy-2-methylpropanamido)phenyl)-2-hydroxy-2-methylpropanamide;N-(4-chloro-2-benzoylphenyl)-2-hydroxy-2-methylpropanamide;N-(2,4-dimethylphenyl)-2-hydroxypropanamide;3-chloro-N-(2,4-dichlorophenyl)-2-hydroxy-2-methylpropanamide and2-hydroxy-2-methyl-N-(2,3,4-trichlorophenyl)propanamide; and saltsthereof;

[0242] and pharmaceutically acceptable in vivo cleavable prodrugs ofsaid compound of formula (I);

[0243] and pharmaceutically acceptable salts of said compound or saidprodrugs.

[0244] According to a further aspect of the present invention there isprovided the use of compounds of the formula (I):

[0245] wherein:

[0246] ring C is as defined in (a) or (b);

[0247] R¹ is as defined in (c) or (d);

[0248] n is 1 or 2;

[0249] R² and R³ are as defined in (e) or (f);

[0250] A-B is as defined in (g) or (h) and

[0251] R⁴ is as defined in (i) or (j)

[0252] wherein

[0253] (a) ring C is phenyl or carbon-linked heteroaryl selected frompyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; wherein said phenyl orheteroaryl is substituted on carbon at one or both positions meta to theposition of A-B attachment or on carbon at the position para to theposition of A-B attachment by P¹ or P² (wherein P¹ and P² are as definedhereinafter), and further, wherein said phenyl or heteroaryl isoptionally substituted on carbon at any remaining meta position(s) orpara position by P¹ or P³, (wherein P¹ and P³ are as definedhereinafter);

[0254] (b) ring C is selected from the following five groups:

[0255] (i) phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl wherein said phenyl or heteroarylis unsubstituted except by (R¹)_(n) wherein R¹ and n are as definedhereinafter;

[0256] (ii) a carbon-linked triazine optionally substituted on a ringcarbon at a position meta or para to A-B attachment by 1 substituentselected from P¹, P², P³ and P⁴, wherein P¹, P², P³ and P⁴ are asdefined hereinafter;

[0257] (iii) a 6-membered carbon-linked heteroaryl group containing 1-3nitrogen atoms wherein one or more ring nitrogen atoms are oxidised toform the N-oxide, which heteroaryl group is optionally substituted atany of the positions meta or para to A-B attachment by 1-3 substituentsselected from P¹, P², P³ and P⁴, wherein P¹, P², P³ and P⁴ are asdefined hereinafter;

[0258] (iv) phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl orheteroaryl is substituted at a position meta or para to A-B attachmentby 1 substituent selected from P³ and P⁴, wherein P³ and P⁴ are asdefined hereinafter; and

[0259] (v) phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl orheteroaryl is substituted at any of the positions meta or para to A-Battachment by 2-3 substituents selected from P¹, P², P³ and P⁴, providedthat if one or more of the substituents is P¹ or P² then at least one ofthe other substituents is P⁴, wherein

[0260] P¹, P², P³ and P⁴ are as defined hereinafter;

[0261] P¹ is cyano, trifluoromethyl, nitro, trifluoromethoxy ortrifluoromethylsulphanyl;

[0262] P² is —Y¹Ar¹, wherein Ar¹ is selected from the group consistingof phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing1-2 heteroatoms selected independently from O, N and S, wherein saidphenyl or heteroaryl ring is optionally substituted at carbon, with 1-4substituents selected from Q¹, wherein Q¹ is as defined hereinafter; andY¹ is selected from —CO—, —SO— and —SO₂—;

[0263] P³ is C₁₋₄alkyl, haloC₂₋₄alkyl, C₁₋₄alkoxy, haloC₂₋₄alkoxy,C₂₋₄alkenyloxy, halo or hydroxy;

[0264] P⁴ is selected from the following five groups:

[0265] 1) halosulphonyl, cyanosulphanyl;

[0266] 2) —X¹—R⁵ wherein X¹ is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR⁶—, —CO—, —COO—, —OCO—, —CONR⁷—, —NR⁸CO—, —OCONR⁹—, —CONR¹⁰SO₂—,—NR¹¹SO₂—, —CH₂—, —NR¹²COO—, —CSNR¹³—, —NR¹⁴CS—, —NR¹⁵CSNR¹⁶—,NR¹⁷CONR¹⁸— or —NR¹⁹CONR²⁰SO₂— (wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁵ is selected fromhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl whichC₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionallysubstituted with one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl with theproviso that P⁴ is not trifluoromethyl, trifluoromethoxy,trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy;

[0267] 3) —X¹—C₁₋₆alkyl-X²—R²¹ wherein X¹ is as defined hereinbefore, X²is a direct bond, —O—, —S—, —SO—, —SO₂—, —NR²²—, —CO—, —COO—, —OCO—,—CONR²³—, —NR²⁴CO—, —NR²⁵COO—, —SO₂NR²⁶—, —NR²⁷SO₂—, —CH₂—, —SO₂NR²⁸CO—,—OCONR²⁹—, —CSNR³⁰—, —NR³¹CS—, —NR³²CSNR³³—, —NR³⁴CONR³⁵—, —CONR³⁶SO₂—,—NR³⁷CONR³⁸SO₂— or —SO₂NR³⁹CONR⁴⁰— (wherein R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹ and R⁴⁰,each independently represents hydrogen, C₁₋₄alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₄alkyl or R⁴¹ wherein R⁴¹is phenyl or a 4-12 membered heterocyclic moiety containing 1-4heteroatoms selected independently from O, N and S which heterocyclicmoiety may be aromatic or non-aromatic and which phenyl or heterocyclicmoiety is optionally substituted by 1-6 substituents selected from Q³wherein Q³ is as defined hereinafter;

[0268] 4) —X¹—C₃₋₇cycloalkyl-X²—R²¹ wherein X¹, X² and R²¹ are asdefined hereinbefore; and

[0269] 5) —Y²Ar² wherein Y² is X¹ wherein X¹ is as defined hereinbeforeand Ar² is selected from the following four groups:

[0270] (i) phenyl, a carbon-linked 6-membered heteroaryl ring containing1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ringcontaining 1-2 heteroatoms selected independently from O, N and S,wherein said phenyl or heteroaryl ring is substituted at carbon, with1-4 substituents selected from Q¹ and Q² including at least onesubstituent selected from Q² wherein Q¹ and Q² are as definedhereinafter;

[0271] (ii) a carbon-linked triazine or a carbon-linked 5-memberedheteroaryl ring containing 3-4 heteroatoms selected independently fromO, N and S; wherein said heteroaryl ring is optionally substituted with1-4 substituents selected from Q¹ and Q² wherein Q¹ and Q² are asdefined hereinafter;

[0272] (iii) a 4-12 membered non-aromatic heterocyclic moiety containing1-4 heteroatoms selected independently from O, N and S wherein saidheterocyclic moiety is optionally substituted with 1-6 substituentsselected from Q³ wherein Q³ is as defined hereinafter, with the provisothat if Ar² is a nitrogen linked heterocyclic ring Y² is not —SO₂—; and

[0273] (iv) Ar¹ with the proviso that if Ar² has a value Ar¹ then Y² isnot —CO—, —SO— or —SO₂—;

[0274] Q¹ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₂₋₄alkenyloxy, cyano, nitro, halo or trifluoromethylsulphanyl;

[0275] Q² is selected from the following seven groups:

[0276] 1) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised);

[0277] 2) halosulphonyl, cyanosulphanyl;

[0278] 3) —X³—R⁵ wherein X³ is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR⁴²—, —CO—, —COO—, —OCO—, —CONR⁴³—, —NR⁴⁴CO—, —NR⁴⁵COO—, —SO₂NR⁴⁶—,—NR⁴⁷SO₂—, —CH₂—, —SO₂NR⁴⁸CO—, —OCONR⁴⁹—, —CSNR⁵⁰—, —NR⁵¹CS—,—NR⁵²CSNR⁵³—, —NR⁵⁴CONR⁵⁵—, —CONR⁵⁶SO₂—, —NR⁵⁷CONR⁵⁸SO₂— or—SO₂NR⁵⁹CONR⁶⁰— (wherein R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰,R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹ and R⁶⁰ each independentlyrepresents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁵ is asdefined hereinbefore but with the proviso that Q² is nottrifluoromethylsulphanyl, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy;

[0279] 4) R⁴¹ wherein R⁴¹ is as defined hereinbefore;

[0280] 5) —X³—C₁₋₆alkyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore;

[0281] 6) —X³—C₃₋₇cycloalkyl-X²—R²¹ wherein X³, X² and R²¹ are asdefined hereinbefore; and

[0282] 7) —X³—R⁴¹ wherein R⁴¹ and X³ are as defined hereinbefore;

[0283] Q³ is selected from the following four groups:

[0284] 1) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised);

[0285] 2) cyano, nitro or halo;

[0286] 3) halosulphonyl, cyanosulphanyl; and

[0287] 4) —X⁴—R⁶¹ wherein X⁴ is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR⁶²—, —CO—, —COO—, —OCO—, —CONR⁶³—, —NR⁶⁴CO—, —NR⁶⁵COO—, —SO₂NR⁶⁶—,—NR⁶⁷SO₂—, —CH₂—, —SO₂NR⁶⁸CO—, —OCONR⁶⁹—, —CSNR⁷⁰—, —NR⁷¹CS—,—NR⁷²CSNR⁷³—, —NR⁷⁴CONR⁷⁵—, —CONR⁷⁶SO₂—, —NR⁷⁷CONR⁷⁸SO₂— or—SO₂NR⁷⁹CONR⁸⁰— (wherein R⁶², R⁶³, R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰,R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁹ and R⁸⁰ each independentlyrepresents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁶¹ isselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl andC₂₋₆alkynyl which C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynylis optionally substituted with one or more groups selected from hydroxy,amino, halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy andhydroxyC₁₋₆alkyl;

[0288] (c) R¹ is linked to ring C at a carbon ortho to the position ofA-B attachment and is selected from the group consisting of C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkenyloxy, cyano, nitro,halo, trifluoromethylsulphanyl and hydroxy;

[0289] (d) R¹ is linked to ring C at a ring carbon atom ortho to theposition of A-B attachment and is selected from the following twogroups:

[0290] 1) —X⁵—R⁸¹ wherein X⁵ is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR⁸²—, —CO—, —COO—, —OCO—, —CONR⁸³—, —NR⁸⁴CO—, —NR⁸⁵COO—, —SO₂NR⁸⁶—,—NR⁸⁷SO₂—, —CH₂—, —SO₂NR⁸⁸CO—, —OCONR⁸⁹—, —CSNR⁹⁰—, —NR⁹¹CS—,—NR⁹²CSNR⁹³—, —NR⁹⁴CONR⁹⁵—, —CONR⁹⁶SO₂—, —NR⁹⁷CONR⁹⁸SO₂— or—SO₂NR⁹⁹CONR¹⁰⁰— (wherein R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁹, R⁹⁰,R⁹¹, R⁹², R⁹³, R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷, R⁹⁸, R⁹⁹ and R¹⁰⁰ each independentlyrepresents hydrogen, C₁₋₄ alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸¹ isselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl andC₂₋₆alkynyl which C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynylis optionally substituted with one or more groups selected from hydroxy,amino, halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy andhydroxyC₁₋₆alkyl with the proviso that R¹ is nottrifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; and

[0291] 2) —X⁶—R¹⁰¹ wherein X⁶ is selected from a direct bond, —CO—, —O—,—OCH₂—, —S—, —SO—, —SO₂— and —NR¹⁰²— (wherein R¹⁰² is hydrogen orC₁₋₄alkyl) and R¹⁰¹ is phenyl which is optionally substituted by 1-4substituents selected from cyano, nitro, trifluoromethylsulphanyl,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₂₋₆alkenyloxy,halo, hydroxy and amino;

[0292] n is, 1 or 2;

[0293] (e) either R² and R³ are independently C₁₋₃alkyl optionallysubstituted by from 1 to 2k+1 atoms selected from fluoro and chlorowherein k is the number of carbon atoms in the said C₁₋₃alkyl, providedthat R² and R³ are not both methyl;

[0294] or R² and R³, together with the carbon atom to which they areattached, form a 3-5 membered cycloalkyl ring optionally substituted byfrom 1 to 2m−2 fluorine atoms wherein m is the number of carbon atoms insaid ring;

[0295] (f) R² and R³ are both methyl or one of R² and R³ is hydrogen orhalo and the other is halo or C₁₋₃alkyl optionally substituted by from 1to 2k+1 atoms selected from fluoro and chloro wherein k is the number ofcarbon atoms in the said C₁₋₃alkyl, with the proviso that when either R²or R³ is halo R⁴ is not hydroxy and with the proviso that when either R²or R³ is hydrogen, R⁴ is not hydrogen;

[0296] (g) A-B is selected from —NHCO—, —OCH₂—, —SCH₂—, —NHCH₂—,trans-vinylene, and ethynylene;

[0297] (h) A-B is —NHCS—or —COCH₂—;

[0298] (i) R⁴ is hydroxy;

[0299] (j) R⁴ is hydrogen, halo or methyl;

[0300] but excluding compounds wherein ring C is selected from (a) andR¹ is selected only from (c) and R² and R³ are selected from (e) and A-Bis selected from (g) and R⁴ is selected from (i); and salts thereof;

[0301] and pharmaceutically acceptable in vivo cleavable prodrugs ofsaid compound of formula (I); and pharmaceutically acceptable salts ofsaid compound or said prodrugs;

[0302] in the manufacture of a medicament for use in the elevation ofPDH activity in warm-blooded animals such as humans.

[0303] In a further aspect of the invention there is provided a compoundof formula (I′):

[0304] wherein:

[0305] n is 1 or 2;

[0306] R^(a) is chloro, fluoro, bromo, nitro or methoxy;

[0307] R^(b) is C₁₋₆alkyl optionally substituted by one or more groupsselected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy orC₁₋₆alkoxy or R^(b) is phenyl, a carbon-linked 6-membered heteroarylring containing 1-2 nitrogen atoms or a carbon-linked 5-memberedheteroaryl ring containing 1-3 heteroatoms selected independently fromO, N and S, wherein said phenyl or heteroaryl ring is substituted by oneor more groups selected from i)-iii) and is optionally furthersubstituted with a group selected from iv):

[0308] i) —X^(a)—R^(c) wherein X^(a) is a direct bond, —O—, —S—, —SO,—SO₂—, —NR^(d)— or —CONR^(e)— (wherein R^(d) and R^(e) eachindependently represents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl isoptionally substituted with one or more groups selected from hydroxy orC₁₋₄alkoxy) and R^(c) is selected from hydrogen or C₁₋₆alkyl whichC₁₋₆alkyl is optionally substituted with one or more hydroxy orC₁₋₄alkoxy with the proviso that —X^(a)—R^(c) is not C₁₋₄alkyl orC₁₋₄alkoxy;

[0309] ii) a 4-12 membered heterocyclic moiety containing 1-4heteroatoms selected independently from O, N and S which heterocyclicmoiety may be aromatic or non-aromatic and is optionally substitutedwith one or more groups selected from hydroxy, halo, C₁₋₄alkoxy,C₁₋₄alkyl or cyano;

[0310] iii) —X^(a)—C₁₋₆alkyl-X^(b)—R^(c) wherein X^(a) and R^(c) are asdefined hereinbefore and X^(b) is —S—, —SO— or —SO₂—;

[0311] iv) cyano, hydroxy, halo, C₁₋₄alkoxy, C₁₋₄alkyl; and

[0312] and salts thereof;

[0313] and pharmaceutically acceptable in vivo cleavable prodrugs ofsaid compound of formula (I);

[0314] and pharmaceutically acceptable salts of said compound or saidprodrugs.

[0315] Preferable values for a compound of formula (I′) are as follows:

[0316] Preferably R^(a) is chloro or fluoro.

[0317] More preferably R^(a) is chloro.

[0318] Preferably R^(b) is C₁₋₄alkyl optionally substituted by one ormore hydroxy or R^(b) is phenyl, a carbon-linked 6-membered heteroarylring containing 1-2 nitrogen atoms or a carbon-linked 5-memberedheteroaryl ring containing 1-2 heteroatoms wherein said phenyl orheteroaryl ring is substituted by one or more groups selected fromi)-iii):

[0319] i) —X^(a)—R^(c) wherein X^(a) is —SO—, —SO₂—, —NR^(d)— or—CONR^(e)— (wherein R^(d) and R^(e) each independently representshydrogen or C₁₋₄alkyl) and R^(c) is selected from hydrogen or C₁₋₆alkylwhich C₁₋₆alkyl is optionally substituted with one or more hydroxy;

[0320] ii) a 4-12 membered heterocyclic moiety containing 1-4heteroatoms selected independently from O, N and S which heterocyclicmoiety may be aromatic or non-aromatic;

[0321] iii) —X^(a)—C₁₋₆alkyl-X^(b)—R^(c) wherein X^(a) and R^(c) are asdefined hereinbefore and X^(b) is —S—.

[0322] More preferably R^(b) is C₁₋₄alkyl optionally substituted byhydroxy or R^(b) is phenyl wherein said phenyl is substituted by onegroup selected from i)-iii):

[0323] i) —X^(a)—R^(c) wherein X^(a) is —SO—, —SO²—, —NR^(d)— or—CONR^(e)— (wherein R_(d) and R^(e) each independently representshydrogen or C₁₋₄alkyl) and R^(c) is selected from hydrogen or C₁₋₄alkylwhich C₁₋₆alkyl is optionally substituted with one or more hydroxy;

[0324] ii) a 4-12 membered heterocyclic moiety containing 1-4heteroatoms selected independently from O, N and S which heterocyclicmoiety may be aromatic or non-aromatic;

[0325] iii) —X^(a)—C₁₋₆alkyl-X¹—R¹ wherein X^(a) and R^(c) are asdefined hereinbefore and X^(b) is —S—.

[0326] Particularly R^(b) is ethyl, 2-hydroxyethyl,4-N,N-dimethylcarbamoylphenyl, 4-(2-hydroxyethlyamino)phenyl,4-methylsulphinylphenyl, 4-mesylphenyl, 4-aminophenyl,4-(2-oxopyrrolidi-1-yl)phenyl and 4-(2-methylthioethylamino)phenyl.

[0327] In one aspect of the invention preferably n is 1.

[0328] In another aspect of the invention preferably n is 2.

[0329] In one aspect of the invention preferably the groupR^(b)—S(O)_(n)— is para to the —NH—C(O)— group.

[0330] In another aspect of the invention preferably the groupR^(b)—S(O)_(n)— is meta to the —NH—C(O)— group.

[0331] Preferably the tertiary centre of formula (I′) —C(OH)(CF₃)(Me)has the R stereochemistry.

[0332] Preferred compounds of formula (I) or (I′) are those of Examples14, 43, 63, 71, 74, 87, 128, 144, 215 and 355 and salts thereof; andpharmaceutically acceptable in vivo cleavable prodrugs of said compoundof formula (I); and pharmaceutically acceptable salts of said compoundor said prodrugs.

[0333] Compounds of the present invention include:

[0334]N-(2,6-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide.

[0335] N-(2-cyanophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0336]N-2-chloro-4-[(2-hydroxy-2-methyl-3,3,3-trifluoropropanamide]phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0337]N-2-nitro-4-[(2-hydroxy-2-methyl-3,3,3-trifluoropropanamide]phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0338]N-[2-(4-chlorobenzoyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0339]N-[2-carboxy-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0340]N-(4-bromo-2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0341]N-(2,4-dichlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0342] N-(2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0343] N-(2-fluorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0344] N-(biphen-2-yl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0345] N-(2-acetylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0346] N-(2-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0347] N-(2-bromophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0348]2-hydroxy-2-methyl-N-[2-(phenylsulphonyl)phenyl]-3,3,3-trifluoropropanamide;

[0349]N-(2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0350]N-(2-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0351](R)—N-(4-bromo-2,6-dichlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0352](R)—N-[2-chloro-4-(phenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0353](S)—N-[2-chloro-4-(phenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0354](R)—N-[2-fluoro-4-(phenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0355](R)—N-(4-bromo-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0356] N-[2-chloro-4-(phenylsulphonyl)phenyl]-2-hydroxypropanamide;

[0357] N-(2-fluoro-4-iodophenyl)-2-hydroxypropanamide;

[0358]N-{4-[(benzyloxycarbonyl)amino]-2-fluorophenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0359]N-[2-(hydroxymethyl)-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0360]N-(4-benzyl-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0361]N-(2-carbamoyl-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0362]N-(4-iodo-2-methoxycarbonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0363]N-(4-iodo-2-nitrophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0364]N-(2-bromo-4-methoxycarbonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0365]N-(4-bromo-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0366]N-[2-chloro-4-(benzoylamino)phenyl]-2-hydroxy-2-methylpropanamide;

[0367]N-2-chloro-4-[(phenylsulphonyl)amino]phenyl-2-hydroxy-2-methylpropanamide;

[0368]N-(4-chloro-2-methoxyphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0369]2-hydroxy-N-(4-methoxy-2-methylphenyl)-2-methyl-3,3,3-trifluoropropanamide;

[0370]N-(2,3-dimethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0371]N-(3-chloro-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0372]N-(4-bromo-2-trifluoromethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0373]N-(4-chloro-2-benzoylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0374]N-(4-chloro-2-trifluoromethylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0375]N-(4-chloro-2-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0376]N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0377]N-(2-chloro-4-mesylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0378]N-(2-chloro-4-fluorosulphonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0379]N-(2,4-diiodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0380]N-(2-bromo-4-methylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0381]N-(2-bromo-4-butylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0382]N-(2-chloro-4-thiocyanatophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0383]N-[2-fluoro-4-(allyloxycarbonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0384]N-[2-fluoro-4-{N-[(1,3-diethoxycarbonyl)propyl]carbamoyl}phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;

[0385] N-(4-amino-2-chlorophenyl)-2-hydroxy-2-methylpropanamide:

[0386]N-[2-chloro-4-(4-aminophenylsulphanyl)phenyl]-2-hydroxy-2-methylpropanamide;

[0387] and Examples 106, 108, 110-113, 149, 151, 171, 173, 197 and 205;

[0388] and salts thereof and pharmaceutically acceptable in vivocleavable esters or sulphides of said compounds; and pharmaceuticallyacceptable salts of said compounds or esters or sulphides.

[0389] Advantageous compounds of the present invention include Examples184-186 and salts thereof and pharmaceutically acceptable in vivocleavable esters or sulphides of said compounds; and pharmaceuticallyacceptable salts of said compounds or esters or sulphides.

[0390] Preferred compounds of the present invention include Examples 15,114, 171, 172 and 182 and salts thereof and pharmaceutically acceptablein vivo cleavable esters or sulphides of said compounds; andpharmaceutically acceptable salts of said compounds or esters orsulphides.

[0391] More preferred compounds of the present invention includeExamples 14 and 87 and salts thereof and pharmaceutically acceptable invivo cleavable esters or sulphides of said compounds; andpharmaceutically acceptable salts of said compounds or esters orsulphides.

[0392] Particular compounds of the present invention include Examples 1,2, 13, 16, 54, 86, 104, 212, 213 and 214 and salts thereof andpharmaceutically acceptable in vivo cleavable esters or sulphides ofsaid compounds; and pharmaceutically acceptable salts of said compoundsor esters or sulphides.

[0393] In another aspect of the invention, preferred compounds of theinvention are any one of Examples 1-428 and salts thereof; andpharmaceutically acceptable in vivo cleavable prodrugs of said compoundof formula (I); and pharmaceutically acceptable salts of said compoundor said prodrugs.

[0394] Preferred aspects of the invention are those which relate to thecompound or a pharmaceutically acceptable salt thereof.

[0395] In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Ananalogous convention applies to other generic terms. Unless otherwisestated the term “alkyl” advantageously refers to chains with 1-6 carbonatoms, preferably 1-4 carbon atoms.

[0396] In this specification the term “alkoxy” refers to an alkyl groupas defined hereinbefore linked to an oxygen atom.

[0397] In this specification the term “cycloalkyl” refers to cyclicnon-aromatic rings of carbon atoms.

[0398] In this specification the term “cycloalkoxy” refers to acycloalkyl group as defined hereinbefore linked to an oxygen atom.

[0399] In this specification the term “halo” includes fluoro, chloro,bromo and iodo unless stated otherwise.

[0400] In this specification the term “haloalkyl” includes an alkylgroup as defined hereinbefore substituted with one or more halo groups,including for example trifluoromethyl.

[0401] In this specification the term “hydroxyalkyl” includes an alkylgroup as defined hereinbefore substituted with one or more hydroxygroups.

[0402] In this specification the term “aryl” includes C₅₋₁₂aromaticgroups which may, if desired and unless otherwise defined, carry one ormore substituents selected from halo, alkyl, alkoxy, cyano, nitro ortrifluoromethyl (wherein alkyl and alkoxy are as hereinbefore defined).Suitable values for aryl include phenyl and naphthyl.

[0403] The term “aryloxy” means an aryl group as defined hereinbeforelinked to an oxygen atom. Suitable values for aryloxy include phenoxyand naphth-1-yloxy.

[0404] The term “heteroaryl” includes aryl groups, as definedhereinbefore, containing one or more heteroatoms selected from O, N andS.

[0405] Suitable values for “a 6-membered carbon-linked heteroaryl groupcontaining 1-3 nitrogen atoms wherein one or more ring nitrogen atomsare oxidised to form the N-oxide” include pyridyl-N-oxide,pyrimidyl-N-oxide and pyrazinyl-N-oxide.

[0406] Suitable values for “a carbon-linked 6-membered heteroaryl ringcontaining 1-2 nitrogen atoms” include pyridyl, pyrimidyl, pyrazinyl andpyridadzinyl.

[0407] Suitable values for “a carbon-linked 5-membered heteroaryl ringcontaining 1-2 heteroatoms selected independently from O, N and S”include furyl, thienyl, pyrrolyl, thiazolyl, isoxazolyl, oxazolyl,imidazolyl and pyrazolyl.

[0408] Suitable values for “a carbon-linked 5-membered heteroaryl ringcontaining 3-4 heteroatoms selected independently from O, N and S”include oxadiazolyl, furazanyl, triazolyl and thiadiazolyl.

[0409] Suitable values for a “5-6 membered heterocyclic aromatic ringcontaining 1-4 heteroatoms selected independently from O, N and S”include furyl, thienyl, pyrrolyl, thiazolyl, isoxazolyl, oxazolyl andpyrazolyl, tetrazolyl, imidazolyl, oxadiazolyl, furazanyl, triazolyl,thiadiazolyl pyridyl, pyrimidyl, pyrazinyl and pyridazinyl.

[0410] Suitable values for a “5-7 membered heterocyclic non-aromaticmoiety containing 1-2 heteroatoms selected independently from O, N andS” include morpholino, piperazinyl, piperidinyl, homopiperazinyl,oxazolidinyl, thiazolinyl, oxaxolinyl, dihydropyranyl and tetrapyranyl.

[0411] Suitable values for “a 5-membered heteroaryl ring containing 1-4heteroatoms selected independently from O, N and S” include pyrrolyl,furyl, thienyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl.

[0412] Suitable values for “a carbon-linked 5-membered heteroaryl ringcontaining 1-3 heteroatoms” include pyrrolyl, furyl, thienyl, pyrazolyl,imidazolyl and triazolyl.

[0413] Suitable values for “a 7-12 membered aromatic heterocyclic moietycontaining 1-4 heteroatoms selected independently from O, N and S”include indolyl, benzofuryl, benzothienyl, benzimidazolyl, purinyl,quinolinyl and isoquinolinyl.

[0414] A “4-12 membered heterocyclic moiety containing 1-4 heteroatomsselected independently from O, N and S which heterocyclic moiety may bearomatic or non-aromatic” is a saturated, partially saturated orunsaturated (including aromatic) mono or bicyclic ring, which may,unless otherwise specified, be carbon or nitrogen linked, and, unlessotherwise specified, any (optional) substituents may be substituents ona ring carbon or nitrogen (where said ring is a ring containing an —NH—moiety the substitution thus replacing the hydrogen), wherein a —CH₂—group can optionally be replaced by a —C(O)—, a ring nitrogen atom mayoptionally bear a C₁₋₆alkyl group and form a quaternary compound or aring nitrogen and/or sulphur atom may be optionally oxidised to form theN-oxide and or the S-oxides. Examples and suitable values of the term“heterocyclic group” are morpholino, piperidyl, pyridyl, pyranyl,pyrrolyl, isothiazolyl, oxazolinyl, oxazolidinyl, indolyl, quinolyl,thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl,pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl,isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone,4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.

[0415] A “4-12 membered non-aromatic heterocyclic moiety containing 1-4heteroatoms selected independently from O, N and S” is as defined in theabove paragraph, but excludes those compounds which are fully aromatic.

[0416] In this specification “non-aromatic” includes fully saturatedrings as well as partially saturated rings but does not include aromaticunsaturated rings.

[0417] The term “heterocyclic” includes aromatic and non-aromatic cyclicmoieties containing one or more heteroatoms selected from O, N and S.

[0418] In this specification unless stated otherwise the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. In this specification unless statedotherwise the term “alkynyl” includes both straight and branched chainalkynyl groups but references to individual alkynyl groups such as2-butynyl are specific for the straight chain version only.

[0419] For the avoidance of any doubt, it is to be understood that whenX¹is, for example, a group of formula —NR⁸CO—, it is the nitrogen atombearing the R⁸ group which is attached to ring C and the carbonyl groupis attached to R⁵, whereas when X¹is, for example, a group of formula—CONR⁷—, it is the carbonyl group which is attached to ring C and thenitrogen atom bearing the R⁷ group is attached to R⁵. When X¹ is—NR¹¹SO₂— it is the nitrogen atom bearing the R¹¹ group which isattached to ring C and the sulphonyl group which is attached to R⁵.Analogous conventions apply to similar groups. When X¹ is —NR⁶— it isthe nitrogen atom bearing the R⁶ group which is linked to ring C and toR⁵. When X¹is —OCO— it is the first oxygen atom which is attached toring C and the carbonyl group is attached to R⁵. When X¹ is —COO— it isthe carbonyl group which is linked to ring C and the other oxygen atomis attached to R⁵. Analogous conventions apply to similar groups. It isfurther to be understood that when X¹ represents —NR⁶— and R⁶ isC₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃alkyl moiety which is linked to thenitrogen atom of X¹ and an analogous convention applies to other groups.

[0420] When X³ is —OCONR⁴⁹— it is the first oxygen which is linked toring Ar² and the carbonyl group while the nitrogen atom is linked to thecarbonyl group, R⁴⁹ and R⁵.

[0421] When X³ is —NR⁴⁷SO₂— it is the nitrogen atom which is linked toAr², R⁴⁷ and the sulphonyl group, and it is the sulphonyl group which islinked to R⁵ and analogous conventions apply to similar groups.

[0422] For the avoidance of any doubt, it is to be understood that whena group C₅₋₆alkyl carries a C₁₋₄alkoxycarbonyl substituent it is thecarbonyl moiety which is attached to C₅₋₆alkyl and an analogousconvention applies to other groups.

[0423] Within the present invention it is to be understood that acompound of the formula (I) or a salt thereof may exhibit the phenomenonof tautomerism and that the formulae drawings within this specificationcan represent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichelevates PDH activity and is not to be limited merely to any onetautomeric form utilized within the formulae drawings. The formulaedrawings within this specification can represent only one of thepossible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

[0424] It will be appreciated by those skilled in the art that certaincompounds of formula (I) contain an asymmetrically substituted carbonand/or sulphur atom, and accordingly may exist in, and be isolated in,optically-active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic or stereoisomericform, or mixtures thereof, which form possesses properties useful in theelevation of PDH activity, it being well known in the art how to prepareoptically-active forms (for example, by resolution of the racemic formby recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, by enzymatic resolution, (forexample WO 9738124), by biotransformation, or by chromatographicseparation using a chiral stationary phase) and how to determineefficacy for the elevation of PDH activity by the standard testsdescribed hereinafter.

[0425] In vivo cleavable prodrugs of compounds of formula (I) includefor example in vivo hydrolysable esters of compounds of the formula (I)containing a carboxy group, for example, a pharmaceutically acceptableester which is hydrolysed in the human or animal body to produce theparent acid, for example, a pharmaceutically acceptable ester formedwith a C₁₋₆alcohol such as methanol, ethanol, ethylene glycol, propanolor butanol, or with a phenol or benzyl alcohol such as phenol or benzylalcohol or a substituted phenol or benzyl alcohol wherein thesubstituent is, for example, a halo (such as fluoro or chloro),C₁₋₄alkyl (such as methyl) or C₁₋₄alkoxy (such as methoxy) group.

[0426] In vivo cleavable prodrugs of compounds of formula (I) alsoinclude for example in vivo hydrolysable amides of compounds of theformula (I) containing a carboxy group, for example, a N—C₁₋₆alkyl orN,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

[0427] It is also to be understood that certain compounds of the formula(I) and salts thereof can exist in solvated as well as unsolvated formssuch as, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which elevate PDHactivity.

[0428] A compound of the formula (I), or salt thereof, and othercompounds of the invention (as hereinafter defined) may be prepared byany process known to be applicable to the preparation ofchemically-related compounds. Such processes include, for example, thoseillustrated in European Patent Applications, Publication Nos. 0524781,0617010, 0625516, and in GB 2278054, WO 9323358 and WO 9738124.

[0429] Another aspect of the present invention provides a process forpreparing a compound of formula (1) or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester thereof, which process (in whichvariable groups are as defined for formula (I) unless otherwise stated)comprises of:

[0430] (a) for compounds of formula (I) where R⁴ is hydroxy:deprotecting a protected compound of formula (II):

[0431] where Pg is an alcohol protecting group;

[0432] (b) for compounds of formula (I) where Y¹, Y² or X¹is —C(O)—:oxidising a corresponding alcohol of formula (III):

[0433] wherein ring D¹ has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by ArCH(OH) and R^(a1) is a group attached to Y¹, Y² orX¹ (possible valued as defined above);

[0434] (c) for compounds of formula (I) where Y¹, Y² or X¹ is —C(O)—:deprotecting a corresponding compound of formula (IV):

[0435] wherein ring D² has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by Ar—C(—O—(CH₂)₃—O—)— and R^(a1) is as defined above;

[0436] (d) for compounds of formula (I) where Ring C has an R^(a2)—CH₂—substituent attached to it wherein R^(a2) is a group that is attachedvia —CH₂— moiety to ring C (possible values as defined above): reductionof a compound of formula (III) or (V):

[0437] wherein ring D¹ has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by ArC(O)—;

[0438] (e) for compounds of formula (I) where ring C has a R^(a3)—C(O)—substituent wherein R^(a3) is and aromatic moiety or alkenyl moiety(possible values as defined above): treating a compound of formula (VI):

[0439] wherein ring D³ has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by G¹ and G¹ is a leaving group; with carbon monoxideand a tin compound having the formula (R⁶)_(p1)Sn(R^(a3))_(p2) (whereinR⁶ is C₁₋₄alkyl and p1+p2=4) or an aluminium compound having the formula(R⁶)_(p3)Al(R^(a3))_(p4) (wherein R⁶ is C₁₋₄alkyl and p3+p4=3);

[0440] (f) for compounds of formula (I) where Ring C has an R^(a4)S(O)—or R^(a4)S(O)₂— substituent. R^(a4) is a group attached through asulphoxide or sulphone moiety (possible values as defined above) and A-Bis not SCH₂ or NHCH₂: oxidising a compound of formula (VI) wherein G¹ isR^(a4)S;

[0441] (g) for a compound of formula (1) in which A-B is —NHC(O)—:coupling compounds of formula (VII):

[0442] wherein J is NH₂, with an acid of formula (VIII):

[0443] wherein X is OH;

[0444] (h) for a compound of formula (I) in which A-B is —NHC(O)—:coupling an aniline of formula (VII) wherein J is —NH₂ with an activatedacid derivative of formula (VIII);

[0445] (i) for a compound of formula (I) in which A-B is —NHC(O)— or—NHC(S)— and R⁴ is hydroxy: reacting a compound of formula (IX):

[0446] wherein X is O or S: with a base to yield the dianion, followedby treatment of the dianion with oxygen in the presence of a reducingagent; or by treatment with a peroxyacid;

[0447] (j) for a compound of formula (I) in which A-B is —NHC(O)—:reacting a compound of formula (VII) wherein J is chloro or fluoro, withan alkali metal amide anion having formula (X):

[0448] wherein M is an alkali metal;

[0449] (k) for a compound of formula (I) that contains no carbonylmoieties, R⁴ is hydroxy and R²═R³: reacting a compound of formula (XI):

[0450] wherein R⁴ is C₁₋₄ alkyl, with a Grignard reagent of formulaR²MgBr or R²MgCl or an organolithium reagent of formula LiR²;

[0451] (l) for a compound of formula (I) that contains no carbonylmoieties and R⁴ is hydroxy: reacting a compound of formula (XII):

[0452] with a compound of formula R²M wherein M is an alkali metal or aGrignard compound of formula R²MgBr or R²MgCl;

[0453] (m) for a compound of formula (I) which has an N-linkedsulphonamide, an N-linked N-alkyl sulphonamide or a sulphinate estersubstituent attached to ring C: treating a corresponding compound offormula (XIII):

[0454] wherein ring D³ has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by G² wherein G² is amino or hydroxy with a sulphonylchloride;

[0455] (n) for a compound of formula (I) in which A-B is ethynylene andR⁴ is not chloro and when R⁴ is hydroxy it is protected: coupling acorresponding compound of formula (VII) wherein J is a leaving group,with a corresponding acetylene of formula (XIV):

[0456] (o) for a compound of formula (I) in which A-B is ethynylene andR⁴ is hydroxy: reacting a corresponding alkyne of formula (XV):

[0457] wherein Z is hydrogen, with a base, followed by treatment with aketone of formula (XVI):

[0458] (p) for a compound of formula (I) in which A-B is trans-vinylene:reducing a corresponding compound of formula (I) in which A-B isethynylene with a suitable reducing agent;

[0459] (q) for a compound of formula (I) in which A-B is trans-vinylene:dehydration of a compound of formula (XVII):

[0460] (r) for a compound of formula (I) in which A-B is trans-vinyleneand R⁴ is hydroxy: base catalysed opening of an epoxide of formula(XVIII):

[0461] (s) for a compound of formula (I) in which A-B is —NHCH₂—:reducing a corresponding compound of formula (I) in which A-B is—NHC(O)—;

[0462] (t) for a compound of formula (I) in which A-B is —OCH₂—, —SCH₂—or —NHCH₂: reacting an ethylene oxide of formula (XIX):

[0463] with a corresponding compound of formula (VII) where J is —OH,—SH or —NH₂;

[0464] (u) for a compound of formula (I) in which A-B is —NHC(S)—:reacting a compound of formula (I) in which A-B is —NHC(O)— with asulphonating reagent;

[0465] (v) a compound of formula (I) in which ring C is substituted byArC(O)— wherein Ar is an aromatic group (possible values as defined forformula (I) above) and A-B is —NHCO—: by acylation of a compound offormula (I);

[0466] w) for a compound of formula (I) in which A-B is —C(O)CH₂— and R⁴is hydroxy: reacting a ketone of formula (XX)

[0467] with a strong base followed by reaction with a ketone of formula(XVI);

[0468] x) for a compound of formula (I) in which A-B is —C(O)CH₂— and R⁴is hydroxy: reaction of a compound of formula (XXI):

[0469] wherein R″ is a C₁₋₆alkyl group, with a ketone of formula (XVI);

[0470] y) for a compound of formula (I) in which A-B is —C(O)CH₂—:reaction of a compound of formula (VII) wherein J is Li with a compoundof formula (XXII):

[0471] z) for a compound of formula (I) in which A-B is —C(O)CH₂—:reaction of a compound of formula (XXIII):

[0472] with a compound of formula (XXIV):

[0473] a1) for compounds of formula (I) where Ring C has an PhS—substituent: treatment of a compound of formula (VI), wherein G¹ is aleaving group, with a thiophenol in the presence of a catalyst;

[0474] b1) for compounds of formula (I) where Ring C has an ArS—substituent wherein Ar as defined above: treating a compound of formula(VI), wherein G¹ is SH with an aromatic compound containing adisplaceable group, in the presence of a catalyst;

[0475] c1) for compounds of formula (I) where Ring C has an ArS—substituent wherein Ar is as defined above and A-B is not NHCO: treatinga compound of formula (VI), wherein G¹ is a leaving group with acompound of formula ArSH in the presence of a base;

[0476] d1) for compounds of formula (I) where ring C has a R^(a2)—NC(O)—substituent wherein R^(a2) is a group that is attached through an amidelinker (possible values as defined above): treating a compound offormula (VI) wherein ring D³ has any of the values defined hereinbeforefor ring C but in which the place of one of the possible substituents onring C is taken by G¹ and G¹ is a leaving group; with carbon monoxideand an amine having the formula —NR^(a2); and

[0477] e1) for compounds of formula (I) where ring C has a R^(a2)—OSO₂—substituent wherein R^(a2) is a group that is attached through asulphinate ester linker (possible values as defined above): treating acompound of formula (VI) wherein ring D³ has any of the values definedhereinbefore for ring C but in which the place of one of the possiblesubstituents on ring C is taken by G¹ and G¹ is a sulphonyl chlorideClO₂S—; with an alcohol having the formula —OR^(a2); and thereafter ifnecessary:

[0478] i) converting a compound of the formula (I) into another compoundof the formula (I);

[0479] ii) removing any protecting groups; or

[0480] iii) forming a pharmaceutically acceptable salt or in vivohydrolysable ester.

[0481] Examples of reactions to convert a compound of the formula (I)into another compound of the formula (I) are known in the art. By way ofillustration these include:

[0482] (i) formation of a hydroxy as a substituent on an aryl orheteroaryl group by cleaving the corresponding alkyl ether or acyloxyester. Convenient methods include, for example, the cleavage of amethoxy group using boron tribromide and the cleavage of a tert-butoxygroup using trifluoroacetic acid; and the cleavage of an acetate groupusing for example lithium hydroxide in a lower alcohol (such as forexample methanol or ethanol);

[0483] (ii) formation of R⁴ as hydroxy. For example, a compound offormula (1) where R⁴ is chloro can be prepared by reaction of a compoundof formula (I) in which R⁴ is hydroxy with a reagent such as thionylchloride in a suitable solvent such as dichloromethane ortetrahydrofuran and at a temperature in the range of 0 to 70° C. Thereaction can optionally be carried out in the presence of a catalystsuch as N,N-dimethylformamide.

[0484] Pg is an alcohol protecting group suitable values for Pg aregroups such as a benzyl groups, silyl groups or a acetyl protectinggroups.

[0485] When G¹ is a leaving group suitable values are bromo, iodo ortriflate.

[0486] Where formula (VIII) is an activated acid derivative, suitablevalues for X include halo (for example chloro or bromo), anhydrides andaryloxys (for example phenoxy or pentafluorophenoxy).

[0487] In formula (X) M is an alkali metal, suitable values for Minclude sodium or lithium. Suitable values for M in formula (XII)include lithium.

[0488] In formula (VII) wherein J is a leaving group suitable values arebromo, iodo or triflate.

[0489] Specific conditions of the above reactions are as follows:

[0490] (a) Examples of suitable reagents for deprotecting an alcohol offormula (II) are:

[0491] 1) when Pg is benzyl:

[0492] (i) hydrogen in the presence of palladium/carbon catalyst, i.e.hydrogenolysis: or

[0493] (ii) hydrogen bromide or hydrogen iodide;

[0494] 2) when Pg is a silyl protecting group:

[0495] (i) tetrabutylammonium fluoride; or

[0496] (ii) aqueous hydrofluoric acid;

[0497] 3) when Pg is acetyl:

[0498] i) mild aqueous base for example lithium hydroxide.

[0499] The reaction can be conducted in a suitable solvent such asethanol, methanol, acetonitrile, or dimethylsulphoxide and mayconveniently be performed at a temperature in the range of −40 to 100°C.

[0500] (b) These conditions are well known in the art for examplesuitable oxidising agents such as pyridinium dichromate and solventssuch as methanol or dichloromethane, may be employed.

[0501] (c) A saturated aqueous acid such as oxalic or a mineral acidsuch as hydrochloric acid or sulphuric acid may conveniently be employedfor this deprotection. The reaction may conveniently be performed at atemperature in the range of 0 to 100° C. in a solvent such as a loweralcohol (e.g. methanol or ethanol), or mixtures of solvent pairs such aswater/dichloromethane, water/tetrahydrofuran or water/acetone.

[0502] (d) Reducing agents such as sodium borohydride (for compounds offormula (V) yielding compounds of formula (III)) and triethylsilane (forcompounds of formula (III)) may be used. A reduction involving sodiumborohydride is conveniently carried out in solvents such as for examplea lower alcohol (e.g. methanol or ethanol) and a reduction usingtriethylsilane is conveniently carried out in a solvent such astrifluoromethylsulphonic acid.

[0503] (e) This reaction with the tin compound is conveniently performedin the presence of a suitable catalyst such as for examplebis(triphenylphosphine)palladium dichloride, and at a temperature in therange of 0 to 100° C. and in a solvent such as for exampletetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, ordimethyl sulphoxide. The reaction with the aluminium compound isconveniently performed in the presence of a similar catalyst andtemperature and in a solvent such as for example diethyl ether, benzene,toluene, or tetrahydrofuran.

[0504] (f) Suitable oxidising agents include potassium permanganate,OXONE, sodium periodate, tert-butyl hydroperoxide (as solution intoluene), peracids (such as for example 3-chloroperoxybenzoic acid),hydrogen peroxide, TPAP (tetrapropylammonium perruthenate) or oxygen.The reaction may be conducted in a suitable solvent such as diethylether, dichloromethane, methanol, ethanol, water, acetic acid, ormixtures of two or more of these solvents. The reaction may convenientlybe performed at a temperature in the range of −40 to 100° C.

[0505] (g) The reaction can be conducted in the presence of a suitablecoupling reagent. Standard peptide coupling reagents known in the artcan be employed as suitable coupling reagents, for exampledicyclohexyl-carbodiimide, optionally in the presence of a catalyst suchas dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in thepresence of a base for example triethylamine, pyridine, or2,6-di-alkyl-pyridines (such as 2,6-lutidine or2,6-di-tert-butylpyridine) or 2,6-diphenylpyridine. Suitable solventsinclude dimethylacetamide, dichloromethane, benzene, tetrahydrofuran,and dimethylformamide. The coupling reaction may conveniently beperformed at a temperature in the range of −40 to 40° C.

[0506] (h) This coupling may be achieved optionally in the presence of abase for example triethylamine, pyridine, 2,6-di-alkyl-pyridines (suchas 2,6-lutidine or 2,6-di-tert-butylpyridine) or 2,6-diphenylpyridine.Suitable solvents include dimethylacetamide, dichloromethane, benzene,tetrahydrofuran, and dimethylformamide. The coupling reaction mayconveniently be performed at a temperature in the range of −40 to 40° C.

[0507] (i) Suitable bases to yield a dianion are strong bases such as alithium dialkylamides (for example lithium diisopropyl amide). Suitablereducing agents include triphenylphosphine. Suitable peroxyacids include3-chloroperoxybenzoic acid. The reactions may conveniently be performedat a temperature in the range of −100° C. to room temperature, in asuitable solvent such as tetrahydrofuran or diethyl ether.

[0508] (j) The reaction may conveniently be performed at a temperaturein the range of −40 to 100° C. and in a suitable solvent such asdimethylformamide, DMSO, or tetrahydrofuran. Where R⁴ is hydroxy thecorresponding dianion is formed.

[0509] (k) The reaction may conveniently be performed at a temperaturein the range of −100 to 20° C., preferably at a temperature in the rangeof −20 to 20° C., in a suitable solvent such as tetrahydrofuran ordiethyl ether.

[0510] (l) The reaction may conveniently be performed at a temperaturein the range of −100 to 25° C. and in a solvent such as tetrahydrofuran,diethyl ether, or 1,2-dimethoxyethane.

[0511] (m) The reaction may be conveniently carried out in the presenceof a base such as for example pyridine, triethylamine or potassiumcarbonate, at a temperature in the range of 0 to 120° C. in a suitablesolvent such as for example N,N-dimethylformamide, or acetonitrile. ForN-linked N-alkylsulphonamides this is followed by alkylation with, forexample, an alkyl iodide or bromide. The alkylation reaction mayconveniently be performed at a temperature in the range of 0 to 120° C.in a suitable solvent such as for example N,N-dimethylformamide, oracetone in the presence of a base such as for example potassiumcarbonate.

[0512] (n) The reaction may be conveniently carried out in the presenceof a catalyst such as a combination of cuprous iodide andbis(triphenyl-phosphine)palladium dichloride or palladium (II) acetate.The reaction can be conducted in an inert solvent such astetrahydrofuran, benzene, or toluene, or in a basic solvent such asdiethylamine (DEA) or triethylamine (TEA), and at a temperature in therange of −20 to 110° C.

[0513] (o) Suitable bases include lithium diisopropylamide (LDA),n-butyllithium or tert-butyllithium. The reaction may be performed at atemperature in the range of −100 to −40° C. preferably at a temperaturein the range of −70 to −40° C. and in a solvent such as tetrahydrofuran,diethyl ether, or 1,2-dimethoxyethane.

[0514] (p) Suitable reducing agents are, for example, lithium aluminiumhydride or sodium bis(methoxyethoxy)aluminium hydride. The reaction canbe conducted in a suitable solvent such as tetrahydrofuran or diethylether, and at a temperature in the range of 0 to 50° C.

[0515] (q) This reaction may be conveniently performed in the presenceof an acid catalyst (for example p-toluenesulphonic acid), in a solventsuch as toluene or dichloromethane at a temperature in the range of 0 to200° C. preferably a temperature in the range of 20 to 100° C.

[0516] (r) The opening may be carried out in a suitable organic solventfor example, ethers or toluene. Ethers such as tetrahydrofuran arepreferred. Suitable bases include potassium tert-butoxide or sodiumhydride. The opening may be carried out at a temperature in the range of−50 to 100° C., preferably at a temperature in the range of 0 to 50° C.

[0517] (s) Suitable reducing agent include lithium aluminium hydride orborane. The reaction can conveniently be carried out at a temperature inthe range of 0° C. to reflux, in solvents such as for example diethylether, tetrahydrofuran, or 1,2-dimethoxyethane.

[0518] (t) Where J is —OH or —SH; the reaction may be convenientlycarried out in the presence of a base for example sodium hydride ortriethylamine. The reaction can be conducted at a temperature of 0° C.to reflux in a solvent such as dichloromethane, tetrahydrofuran, ordiethyl ether. Where J is —NH₂; the reaction may be conveniently carriedout by the procedure as described in JOC (1999), 64, p.287-289 usingcopper (I) triflate as a catalyst.

[0519] (u) Suitable sulphonating reagents are for example phosphoruspentasulphide or Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide).The reaction may optionally be carried out in the presence of a suitablebase such as for example pyridine or triethylamine. Suitable solventsfor the reaction include for example toluene, tetrahydrofuran,1,3-dioxane or acetonitrile. The reaction is conveniently performed at atemperature in the range of from 0° C. to reflux.

[0520] (v) Acylating reagents such as carboxylic acids, or derivativesthereof, may be employed in the presence of the appropriate activatingreagent such as for example polyphosphoric acid. The reaction mayconveniently be performed at a temperature in the range of 0 to 200° C.employing a solvent such as N,N-dimethylformamide,1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidinone, DMSO, or ethyleneglycol if required, followed by (2) the formation of an amide asdescribed in (g) or (h) hereinbefore (Staskum, B., J. Org. Chem. (1964),29, 2856-2860; Ohnmacht C., J. Med. Chem. (1996), 39, 4592-4601).

[0521] (w) suitable strong bases are for example:

[0522] i) sodium hydride in a suitable solvent such as tetrahydrofuranor N,N-dimethylformamide. The reaction is conveniently performed at atemperature in the range of from −78° C. to 25° C.

[0523] ii) lithium diisopropylamide in a suitable solvent such astetrahydrofuran. The reaction is conveniently performed at a temperaturein the range of from −78 to 25° C.

[0524] (x) R″ is preferably methyl. This reaction may be carried out inthe presence of a Lewis acid such as titanium tetrachloride in asuitable solvent such as dichloromethane. This reaction is convenientlyperformed at a temperature in the range of −78 to 50° C.

[0525] (y) This reaction is preferably carried out in a suitablesolvent, for example tetrahydrofuran at a temperature of −78 to 100 ° C.

[0526] z) This reaction is conveniently performed under standard FriedelCrafts conditions, for example in the presence of aluminium trichloridein a solvent such as dichloromethane or nitrobenzene at a temperature of0 to 150° C.

[0527] a1) Suitable catalysts includetetrakis(triphenylphosphine)palladium(0), cuprous chloride or astoichiometric amount of cupurous oxide. The reaction may convenientlybe conducted in a suitable inert solvent such as a lower alcohol, amixture of pyridine and quinoline, dimethylformamide,N-methylpyrrolidinone or toluene and optionally in the presence of abase such as for example sodium methoxide or potassium carbonate.

[0528] b1) Suitable displaceable groups include halo or triflate.Suitable catalysts include tetrakis(triphenylphosphine)palladium(0),cuprous chloride or a stoichiometric amount of cupurous oxide. Thereaction may conveniently be conducted in a suitable inert solvent suchas a lower alcohol or a mixture of pyridine and quinoline orN-methylpyrrolidinone or dimethylformamide and in the presence of a basesuch as for example sodium methoxide if required at a temperature of 25-180° C.

[0529] c1) A suitable leaving group is fluoro. A suitable base ispotassium carbonate. The reaction may conveniently be performed at atemperature in the range of 30 to 200° C. and in a solvent such asN,N-dimethylformamide,1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidinone, DMSO, or ethyleneglycol.

[0530] d1) This reaction with an amine is conveniently performed in thepresence of a suitable catalyst such as for examplebis(triphenylphosphine)palladium dichloride ordichiorobis-(triphenylphosphine) palladium(II), and at a temperature inthe range of 0° C. to reflux and in a solvent such as for exampletetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,dimethyl sulphoxide or using an amine as the required solvent such asfor example tributylamine.

[0531] e2) The reaction may be conveniently carried out in the presenceof a base such as for example pyridine, triethylamine or potassiumcarbonate, at a temperature in the range of 0 to 120° C. in a suitablesolvent such as for example dichloromethane, diethyl ether,N,N-dimethylformamide, or acetonitrile.

[0532] If not commercially available, the necessary starting materialsfor the procedures such as that described above may be made byprocedures which are selected from standard organic chemical techniques,techniques which are analogous to the synthesis of known, structurallysimilar compounds, or techniques which are analogous to the abovedescribed procedure or the procedures described in the examples.

[0533] For example, it will be appreciated that certain of the optionalaromatic substituents in the compounds of the present invention may beintroduced by standard aromatic substitution reactions or generated byconventional functional group modifications either prior to orimmediately following the processes mentioned above, and as such areincluded in the process aspect of the invention. Such reactions andmodifications include, for example, introduction of a substituent bymeans of an aromatic substitution reaction, reduction of substituents,alkylation of substituents and oxidation of substituents. The reagentsand reaction conditions for such procedures are well known in thechemical art. Particular examples of aromatic substitution reactionsinclude the introduction of a nitro group using concentrated nitricacid, the introduction of an acyl group using, for example, anacylhalide and Lewis acid (such as aluminium trichloride) under FriedelCrafts conditions; the introduction of an alkyl group using an alkylhalide and Lewis acid (such as aluminium trichloride) under FriedelCrafts conditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by, for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonylusing, for example, hydrogen peroxide in acetic acid with heating or3-chloroperoxybenzoic acid.

[0534] Specific examples of the techniques used to make the startingmaterials described above are illustrated, but not limited by, thefollowing examples in which variable groups are as defined for formula(I) unless otherwise stated.

[0535] 1) Preparation of Compounds of Formula (II)

[0536] a) compounds of formula (II) in which A-B is —OCH₂—, —SCH₂— or—NHCH₂—may be made by treating the corresponding compound of formula(VII) wherein J is —OH, —SH or —NH₂ with a compound of formula (XXV):

[0537] where Z is a leaving group for example mesylate; in the presenceof a base such as an alkali metal hydride (e.g. sodium hydride), in asolvent such as tetrahydrofuran, dimethyl sulphoxide,N,N-dimethylformamide or1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and at a temperatureof room temperature to reflux.

[0538] A compound of formula (XXV), wherein Z is mesylate may beprepared by reacting a compound of formula (XXV) wherein Z is OH withmethanesulphonyl chloride in the presence of a base such astriethylamine, in a solvent such as dichloromethane, and at atemperature of about −78 to 25° C.

[0539] Compounds of formula (XXV) wherein Z is OH are prepared byreducing a compound of formula (VIII) wherein X is OH and R⁴ is aprotected hydroxy group or a compound of formula (XXVI):

[0540] where E is a carboxy protecting group (e.g. Me) and R⁴ is aprotected hydroxy group with a suitable reducing agent such as lithiumaluminium hydride in a solvent such as diethyl ether or tetrahydrofuranand at a temperature of about 0 to about 25° C.

[0541] b) A compound of formula (II), wherein A-B is —NHC(O)—, may bemade by coupling a compound of formula (VII) wherein J is —NH₂ with acompound of formula (VIII) wherein X is OH and R⁴ is a protected hydroxygroup in a manner analogous to that described for procedure (g) or (h)of preparations of a compound of formula (I) hereinabove. Compounds offormula (VIII) wherein X is OH and R⁴ is a protected hydroxy group maybe made by conventional procedures. For example, cleavage of the estergroup of a compound of formula (XXVI) where E is a carboxy protectinggroup (e.g. Me), under standard conditions such as mild alkalineconditions, for example, aqueous lithium hydroxide.

[0542] Compounds of formula (XXVI) where R⁴ is protected hydroxy may beprepared by protecting a compound of formula (XXVI) where R⁴ is hydroxyby reaction with a compound such as benzyl chloride or benzyl bromide(in the presence of a suitable base such as sodium hydride andoptionally with a catalyst such as sodium or ammonium iodide, to providea benzyl protecting group) or any of the conventional silylating agentsknown and used for such purpose (for example2-trimethylsilylethoxymethyl chloride, in the presence of a suitablebase such as triethylamine optionally in the presence of a catalyst suchas N,N-dimethylaminopyridine).

[0543] Compounds of formula (XXVI) where R⁴ is hydroxy are prepared byesterifying an acid of formula (VIII) wherein X is OH by a conventionalesterification procedure such as reaction with a C₁₋₆alcohol (e.g.methanol) in the presence of an acid catalyst (for example sulphuricacid).

[0544] c) A compound of formula (II), wherein A-B is ethynylene, may bemade by reacting a compound of formula (VII) wherein J is a leavinggroup such as bromo, iodo, or triflate, with an acetylene of formula(XXVII)

[0545] wherein if R⁴ is protected hydroxy in the presence of a catalystsuch as a combination of copper (I) iodide andbis(triphenylphosphine)palladium dichloride or palladium (II) acetate.The reaction can be conducted in an inert solvent such astetrahydrofuran, benzene, or toluene, or in a basic solvent such asdiethylamine or triethylamine, and at a temperature in the range of −20to 110° C.

[0546] A compound of formula (XXVII) wherein R⁴ is a protected hydroxygroup may be made by reacting a compound of formula (XXVII) where R⁴ isOH with a conventional hydroxy protecting group reagent such as thosedescribed herein before and herein after.

[0547] d) A compound of formula (II), wherein A-B is trans-vinylene, maybe made by reacting a compound of formula (XXVIII):

[0548] where M is an alkylmetal group such as a trialkyltin (for exampletributyl- or trimethyl-tin) or a bisalkyloxyborane (for examplecatecholborane) and R⁴ is protected hydroxy with a compound of formula(VII), wherein J is a leaving group for example iodide, bromide ortriflate in the presence of a catalyst such asbis(triphenylphosphine)palladium dichloride ortetrakis(triphenylphosphine)palladium (0). The reaction may convenientlybe conducted in a suitable inert solvent such as a tetrahydrofuran ordimethylformamide at a temperature of 0-150° C. under an inertatmosphere.

[0549] A compound of formula (XXVIII) may be made by a reaction of acompound of formula (XXVII)

[0550] i) with an agent such as catecholborane, to form the vinylboranecompound of formula (XXVIII) where M is catecholborane; or

[0551] ii) a trialkyltinhydride in the presence of a catalytic amount ofa radical chain initiator such as, for example, aza-bis-isobutyronitrileor by using trialkyltinhydride pre-treated with a strong base (such asan alkyllithium) and copper (I) cyanide, or by using a transition metalcatalyst such as, for example, tetrakis(triphenylphosphine)palladium(0)to form a compound of formula (XXVIII) where M is trialkyltin.

[0552] These reactions may conveniently be conducted in a suitable inertsolvent such as tetrahydrofuran, toluene or xylene at a temperature offrom 0-150° C. under an inert atmosphere.

[0553] Compounds of formula (XXVII) may be made by reacting a compoundof formula (XVI) with an alkali metal acetylide (for example lithiumacetylide) or alkaline earth metal acetylide (for example magnesiumacetylide). The reaction may be conducted in a solvent such astetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane and at atemperature of −100 to 25° C.

[0554] 2) Preparation of a Compound of Formula (IV):

[0555] a) A compound of formula (IV), wherein A-B is ethynylene and R⁴is OH, may be made by reacting a corresponding compound of formula(XXIX):

[0556] wherein ring D⁵ has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by Ar(—C—O—(CH₂)₃—O—)— with a base such as analkyllithium (for example, butyllithium) followed by addition of aketone having the formula (XVI). The reaction may be conducted at atemperature of from about −100 to about −40° C. and in a solvent such astetrahydrofaran, dimethyl ether, or 1,2-dimethoxyethane.

[0557] b) A compound of formula (IV), wherein A-B is trans-vinylene, maybe made by reducing a corresponding compound of formula (IV), whereinA-B is ethynylene, with a suitable reducing agent such as lithiumaluminium hydride or sodium bis(2-methoxyethoxy)aluminium, in a solventsuch as tetrahydrofuran. The reaction may be conducted at a temperatureof from about −40 to about 40° C.

[0558] c) a compound of formula (XXIX) may be made by treating thecorresponding ketone with 1,3-propanediol in the presence of an acidcatalyst such as p-toluenesulphonic acid (TsOH) and in a refluxingsolvent such as toluene using a Dean Stark apparatus or dried MolecularSives.

[0559] 3) Preparation of a Compound of Formula (VI):

[0560] a) A compound of formula (VI) wherein G¹ is halo, such as forexample bromo or iodo may be made by (1) treating a correspondingcompound of formula (VI), wherein G¹ is nitro, with a reducing agentsuch as tin(II)chloride, in the presence of an aqueous acid such asacetic acid to obtain the corresponding amine, followed by (2) treatingthe amine with a combination of nitric acid and sulphuric acid ortert-butyl nitrite to effect diazotization, and thereafter (3) treatingthe diazotized compound with a corresponding copper(I)halide such as forexample cuprous bromide or potassium iodide.

[0561] b) A compound of formula (VI), wherein G¹ is SH can be made by:

[0562] (1) coupling of a compound of formula (VI) wherein G¹ is aleaving group such as halo or triflate with triisopropylsilanethiolateunder palladium catalysis as described by Arnould et. al. in Tet. Let.(1996), 37 (26), p. 4523, followed by deprotection withtetrabutylammonium fluoride in a solvent such as tetrahydrofuran at atemperature of −78 to about 25° C.; or

[0563] (2) by Pummerer rearrangement as described in Tet. Let. (1984),25 (17), p. 1753 of a compound of formula (VI) wherein G¹ is CH₃S(O)—,which can be made from a compound of formula (VI) wherein G¹ is aleaving group such as halo of triflate, using a palladium catalysedcoupling with methanethiol as described for example in Zheng et. al. inJ. Org. Chem. (1998), 63, p. 9606 followed by an oxidation of theresulting sulphide to the corresponding sulphoxide using, for example,tert-butyl hydroperoxide as oxidant; or

[0564] (3) reduction of a compound of formula (VI), wherein G¹ is SO₂Cl,by reducing the sulphonyl chloride using a small excess of for exampletriphenylphosphine in a solvent such as, for example, dichloromethane inthe presence of a catalyst such as, for example, dimethylformamide,followed by an acidic workup.

[0565] c) a compound of formula (VI), wherein G¹ is SO₂Cl can be made bytreatment with chlorosulphonic acid of a compound of formula (VI),wherein G¹ is H, under standard conditions.

[0566] 4) Preparation of Compounds of Formula (XII)

[0567] A compound of formula (XII), wherein A-B is ethynylene, may bemade by treating a corresponding compound of formula (XV) wherein Z is aprotecting group such as, for example, trimethylsilyl with a fluoridebase (for example, tetrabutylammonium fluoride (TBAF)) and an acidchloride of formula R³—CO—Cl, thereby making the desired compound.

[0568] 5) Preparation of Compounds of Formula (VII)

[0569] A compound of formula (VII), wherein J is halo, may be made bytreating a corresponding compound of formula (VII), wherein J is nitro,with (1) as tin (II) chloride or (2) iron dust and concentratedhydrochloric acid in 95% ethanol to reduce the nitro group and therebyform the corresponding amine; (2) the amine may then be treated forexample with a nitrite (such as tert-butyl nitrite or sodium nitrite inthe presence of a mineral acid) to form the corresponding diazonium saltwhich may in turn be treated with a copper(I) salt (such ascopper(I)bromide or copper(I)chloride) or potassium iodide. Thediazotization and displacement reactions may be conducted in a solventsuch as acetonitrile and at a temperature of from 0 to 25° C.

[0570] 6) Preparation of Compounds of Formula (XIV)

[0571] A compound of formula (XIV) wherein R⁴ is OH may be made byreacting a corresponding ketone having the formula (XVI) with an alkalimetal acetylide (for example lithium acetylide) or alkaline earth metalacetylide (for example magnesium acetylide). The reaction may beconducted in a solvent such as tetrahydrofuran, diethyl ether, or1,2-dimethoxyethane and at a temperature of about −100 to about 25° C.

[0572] 7) Preparation of Compounds of Formula (XIII).

[0573] A compound of formula (XIII), wherein G² is amino and A-B is NHCOmay be made by treating a compound of formula (XIII), wherein G² isnitro, under standard conditions for example by a reducing agent such astin (II) chloride or iron dust in conjunction with concentrated acid, orusing palladium metal supported on charcoal and hydrogen gas in asolvent such as a lower alcohol (methanol or ethanol) or ethyl acetate.

[0574] 8) Preparation of Compounds of Formula (VII)

[0575] i) a compound of formula (VII) wherein R¹ is ortho-halo orortho-hydroxy and J is —NH₂, may be made by treatment of a compound offormula (XXX):

[0576] wherein the amino group is in a position ortho to the nitrogroup, with (1) a combination of nitric acid and sulphuric acid ortert-butyl nitrite to effect diazotization, and thereafter (2) treatingthe diazotized compound with a corresponding copper (I) halide such asfor example cuprous bromide or chloride, or heating in dilute sulphuricacid to form the corresponding phenol, followed by (3) reduction of thenitro group (see 8) ii) or 7)). The diazotization and displacementreactions may be conducted in a solvent such as acetonitrile and at atemperature of from 0-25° C. A compound of formula (XXX) may be made forexample according to procedures similar to those described in J. Med.Chem., (1975), 18, 1164.

[0577] ii) a compound of formula (VII) wherein J is NH₂ may be preparedby reducing a compound of formula (XXXI):

[0578] under standard conditions for example by a reducing agent such astin (II) chloride or iron dust in conjunction with concentrated acid, orusing palladium metal supported on charcoal and hydrogen gas in asolvent such as a lower alcohol (methanol or ethanol) or ethyl acetate.

[0579] iii) a compound of formula (VII) wherein J is NH₂, R¹ is —NO₂ andring C is substituted by ArSO₂: reacting a compound of formula (XXXII):

[0580] wherein ring D⁴ has any of the values defined hereinbefore forring C but in which the place of one of the possible substituents onring C is taken by ArSO₂, with nitric acid, followed by treating thenitrated compound under mild alkaline conditions (i.e. employing a basesuch as lithium hydroxide) to cleave the acetate group to yield theamine.

[0581] iv) a compound of formula (VII) wherein J is —OH, may be preparedby diazotizing a compound of formula (VII) wherein J is —NH₂ understandard conditions followed by heating the resulting compound in dilutesulphuric acid.

[0582] v) a compound of formula (VII), wherein J is —SH, may be preparedby reacting a compound of formula (VII) where J is a leaving group (forexample fluoro or chloro) with an excess of methanethiol in the presenceof sodium hydride.

[0583] vi) a compounds of formula (VII) wherein J is Li may be preparedby

[0584] a) halogen metal exchange. For example by treatment of a compoundof formula (VII) wherein J is Br or I; with an organolithium reagentsuch as n-butyl lithium or t-butyllithium in a solvent such astetrahydrofuran at low temperature such as −100-−50° C.

[0585] b) for compounds where R¹ is an ortho directing metallatingsubstituent by treatment of a compound of formula (XXIII) with an alkyllithium base. Reactions of this type are reviewed in V. Snieckus, ChemRev, 1990, 90, 879-933.

[0586] 9) Resolution of Compounds of Formula (VIII) wherein X is OH

[0587] If the resolved acid is required it may be prepared by any of theknown methods for preparation of optically-active forms (for example, byrecrystallization of the chiral salt {for example WO 9738124}, byenzymatic resolution, by biotransformation, or by chromatographicseparation using a chiral stationary phase). For example if an (R)-(+)resolved acid is required it may be prepared by the method of Scheme 2in World Patent Application Publication No. WO 9738124 for preparationof the (S)-(−) acid, i.e. using the classical resolution methoddescribed in European Patent Application Publication No. EP 0524781,also for preparation of the (S)-(−) acid, except that (1S,2R)-norephedrine may be used in place of (S)-(−)-1-phenylethylamine.

[0588] 10) Preparation of Compounds of Formula (XV)

[0589] A compound of formula (XV) wherein Z is H, may be prepared byreacting a compound of formula (VII), wherein J is a leaving group suchas bromo, iodo or triflate with trimethylsilylacetylene in the presenceof a catalyst such as a combination of bis(triphenylphosphine)palladiumdichloride and copper(I) iodide in diethylamine or triethylamine,followed by treatment with a base (for example potassium carbonate) in aC₁₋₆alcohol (such as methanol) as the solvent to remove thetrimethylsilyl group.

[0590] 11) Preparation of Compounds of Formula (XVII).

[0591] A compound of formula (XVII) may be prepared from a compound offormula (XXXIII):

[0592] by reduction under standard conditions for example by using ahydride, such as sodium borohydride.

[0593] A compound of formula (XXXIII) may be prepared by deprotonationof a compound of formula (VII) where J is Me, with a strong base, forexample lithium diisopropyl amide in an organic solvent, for exampletetrahydrofuran at a temperature of −78 to 100° C. followed by additionof an amide of formula (XXXIV):

[0594] in which R¹⁹ and R²⁰ are each independently C₁₋₆alkyl, preferablymethyl, or together with the atoms to which they are attached form a 5-7membered ring.

[0595] An amide of formula (XXXIV) may be prepared from an acid offormula (VIII), or a reactive derivative thereof, by reaction with ahydroxyamine of formula R¹⁹(R²⁰O)NH under standard conditions such asthose described in process (g) or (h) for preparation of a compound offormula (I) hereinabove.

[0596] 12) Preparation of Compounds of Formula (XVIII)

[0597] A compound of formula (XVIII) may be prepared from a diol offormula (XXXV):

[0598] using a suitable dehydrating agent, for examplebis[α,α-bis(trifluoromethyl)benzene methanolato]diphenyl sulphur.

[0599] 13) Preparation of Compounds of Formula (XIX)

[0600] A compound of formula (XIX) may be made by treating a compound offormula (XVI) with a trimethylsulphonium salt (such astrimethylsulphonium iodide) and a base (such as an alkali metalhydroxide) in a solvent such as dichloromethane.

[0601] 14) Preparation of Compounds of Formula (XX)

[0602] Compounds of formula (XX) can be made by synthetic reactions wellknown in the art for example:

[0603] i) a Friedel Crafts acylation of a compound of formula (XXIII)with acetyl chloride under conditions such as those described in (z)above.

[0604] ii) reaction of a compound of formula (VII) wherein J is Li withan amide of formula (XXXVI):

[0605] under conditions such as those described in 8)vi)b) hereinabove.

[0606] iii) oxidation of a compound of formula (XXXVII):

[0607] 15) Preparation of Compounds of Formula (XXI)

[0608] Compounds of formula (XXI) can be prepared from compounds offormula (XX) by treatment with a base such as lithium diisopropylamideor triethylamine and a silylating agent such as trimethylsilyl chloridein a solvent such as tetrahydrofuran or trimethylsilyl triflate in asolvent such as dichloromethane. The reaction can conveniently beperformed at a temperature in the range of −78 to 70° C.

[0609] 16) Preparation of Compounds of Formula (XXII)

[0610] Compounds of formula (XXII) can be prepared from an acid offormula (XXXVIII):

[0611] or a reactive derivative thereof, by reaction with a hydroxyamineof formula R¹⁹(R²⁰O)NH under standard conditions such as those describedin process (g) or (h) for preparation of a compound of formula (I)hereinabove.

[0612] According to a further feature of the invention, there isprovided a process for preparing a compound of formula (I′) using anyone of processes a), f), g), h), i) or l); and thereafter if necessary:

[0613] i) converting a compound of the formula (I′) into anothercompound of the formula (I′);

[0614] ii) removing any protecting groups; or

[0615] iii) forming a pharmaceutically acceptable salt or in vivocleavable ester.

[0616] It is noted that many of the starting materials for syntheticmethods as described above are commercially available and/or widelyreported in the scientific literature, or could be made fromcommercially available compounds using adaptations of processes reportedin the scientific literature.

[0617] It will also be appreciated that in some of the reactionsmentioned herein it may be necessary/desirable to protect any sensitivegroups in the compounds. The instances where protection is necessary ordesirable and suitable methods for protection are known to those skilledin the art. Thus, if reactants include groups such as amino, carboxy orhydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

[0618] A suitable protecting group for an amino or alkylamino group is,for example, an acyl group, for example an alkanoyl group such asacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group,for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.The deprotection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl group or an aroyl group maybe removed for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

[0619] A suitable protecting group for a hydroxy group is, for example,an acyl group, for example an alkanoyl group such as acetyl, an aroylgroup, for example benzoyl, or an arylmethyl group, for example benzyl.The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

[0620] A suitable protecting group for a phenol is, for example, analkylether, for example, methyl, a silyl ether, for example,trimethylsilyl ether or t-butyldimethylsilyl ether, an oxyalkylether,for example, methoxymethyl ether or methoxyethoxymethyl ether or anester, for example acetate or benzoate. The deprotection conditions forthe above protecting groups will necessarily vary with the choice ofprotecting group. Thus, for example, an alkylether may be removed bytreatment with a suitable reagent such as iodotrimethylsilane or asuitable Lewis acid such as borontribromide. Alternatively a silyl ethermay be removed by acid- or fluoride ion-catalysed hydrolysis.Alternatively oxyalkylethers may be removed by treatment with a suitableacid such as acetic acid or hydrochloric acid. Alternatively esters maybe removed by hydrolysis by a suitable acid or a suitable base.

[0621] A suitable protecting group for a carboxy group is, for example,an esterifying group, for example a methyl or an ethyl group which maybe removed, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

[0622] The protecting groups may be removed at any convenient stage inthe synthesis using conventional techniques well known in the chemicalart.

[0623] In cases where compounds of formula (I) are sufficiently basic oracidic to form stable acid or basic salts, administration of thecompound as a salt may be appropriate, and pharmaceutically acceptablesalts may be made by conventional methods such as those describedfollowing. Examples of suitable pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form aphysiologically acceptable anion, for example, tosylate,methanesulphonate, acetate, tartrate, citrate, succinate, benzoate,ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganicsalts may also be formed such as sulphate, nitrate, and hydrochloride.

[0624] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound of formula (I) (or its ester) with a suitable acidaffording a physiologically acceptable anion. It is also possible withmost compounds of the invention to make a corresponding alkali metal(e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g.,calcium) salt by treating a compound of formula (I) (and in some casesthe ester) with one equivalent of an alkali metal or alkaline earthmetal hydroxide or alkoxide (e.g. the ethoxide or methoxide in aqueousmedium followed by conventional purification techniques.

[0625] In vivo cleavable esters of compounds of the invention may bemade by coupling with a pharmaceutically acceptable carboxylic acid oran activated derivative thereof. For example, the coupling may becarried out by treating a compound of formula (1) with an appropriateacid chloride (for example, acetyl chloride, propionyl chloride, orbenzoyl chloride) or acid anhydride (for example, acetic anhydride,propionic anhydride, or benzoic anhydride) in the presence of a suitablebase such as triethylamine. Those skilled in the art will appreciatethat other suitable carboxylic acids (including their activatedderivatives) for the formation of in vivo cleavable esters are known tothe art and these are also intended to be included within the scope ofthe invention. Catalysts such as 4-dimethylaminopyridine may also beusefully employed.

[0626] Many of the intermediates defined herein are novel and these areprovided as a further feature of the invention.

[0627] The identification of compounds which elevate PDH activity is thesubject of the present invention. These properties may be assessed, forexample, using one or more of the procedures set out below:

[0628] (a) In vitro Elevation of PDH Activity

[0629] This assay determines the ability of a test compound to elevatePDH activity. cDNA encoding PDH kinase may be obtained by PolymeraseChain Reaction (PCR) and subsequent 25 cloning. This may be expressed ina suitable expression system to obtain polypeptide with PDH kinaseactivity. For example rat PDHkinaseII (rPDHKII) obtained by expressionof recombinant protein in Escherichia coli (E. Coli), was found todisplay PDH kinase activity.

[0630] In the case of the rPDHKII (Genbank accession number U10357) a1.3 kb fragment encoding the protein was isolated by PCR from rat livercDNA and cloned into a vector (for example pQE32—Quiagen Ltd.). Therecombinant construct was transformed into E. coli (for exampleM15pRep4—Quiagen Ltd.). Recombinant clones were identified, plasmid DNAwas isolated and subjected to DNA sequence analysis. One clone which hadthe expected nucleic acid sequence was selected for the expression work.Details of the methods for the assembly of recombinant DNA molecules andthe expression of recombinant proteins in bacterial systems can be foundin standard texts for example Sambrook et al, 1989, Molecular Cloning—ALaboratory Manual, 2^(nd) edition, Cold Spring Harbour Laboratory Press.Other known PDH kinases for use in assays, may be cloned and expressedin a similar manner.

[0631] For expression of rPDHKII activity, E. coli strain M15pRep4 cellswere transformed with the pQE32 vector containing rPDHKII cDNA. Thisvector incorporates a 6-His tag onto the protein at its N-terminus. E.coli were grown to an optical density of 0.6 (600 nM) and proteinexpression was induced by the addition of 10 μMisopropylthio-β-galactosidase. Cells were grown for 18 hours at 18° C.and harvested by centrifugation. The resuspended cell paste was lysed byhomogenisation and insoluble material removed by centrifugation at24000×g for 1 hour. The 6-His tagged protein was removed from thesupernatant using a nickel chelating nitrilotriacetic acid resin(Ni—NTA: Quiagen Ltd.) matrix (Quiagen) which was washed with 20 mMtris(hydroxymethyl)aminomethane-hydrogen chloride, 20 mM imidazole, 0.5M sodium chloride pH 8.0, prior to elution of bound protein using abuffer containing 20 mM tris(hydroxymethyl)aminomethane-hydrogenchloride, 200 mM imidazole, 0.15 M sodium chloride pH 8.0. Elutedfractions containing 6-His protein were pooled and stored in aliquots at−80° C. in 10% glycerol.

[0632] Each new batch of stock enzyme was titrated in the assay todetermine a concentration giving approximately 90% inhibition of PDH inthe conditions of the assay. For a typical batch, stock enzyme wasdiluted to 7.5 μg/ml.

[0633] For assay of the activity of novel compounds, compounds werediluted with 10% dimethylsulphoxide (DMSO) and 10 μl transferred toindividual wells of 96-well assay plates. Control wells contained 20 μl10% DMSO instead of compound. 40 μl Buffer containing 50 mM potassiumphosphate buffer pH 7.0, 10 mM ethylene glycol-bis(β-aminoethylether)-N,N,N,N-tetracetic acid (EGTA), 1 mM benzamidine, 1 mMphenylmethylsulphonyl fluoride (PMSF), 0.3 mM tosyl-L-lysinechloromethyl ketone (TLCK), 2 mM dithiothreitol (DTT), recombinantrPDHKII and compounds were incubated in the presence of PDH kinase atroom temperature for 45 minutes. In order to determine the maximum rateof the PDH reaction a second series of control wells were includedcontaining 10% DMSO instead of compound and omitting rPDHKII. PDH kinaseactivity was then initiated by the addition of 5 μM ATP, 2 mM magnesiumchloride and 0.04 U/ml PDH (porcine heart PDH Sigma P7032) in a totalvolume of 50 μl and plates incubated at ambient temperature for afurther 45 minutes. The residual activity of the PDH was then determinedby the addition of substrates (2.5 mM coenzyme A. 2.5 mM thiaminepyrophosphate (cocarboxylase), 2.5 mM sodium pyruvate, 6 mM NAD in atotal volume of 80 μl and the plates incubated for 90 minutes at ambienttemperature. The production of reduced NAD (NADH) was established bymeasured optical density at 340 nm using a plate readingspectrophotometer. The ED₅₀ for a test compound was determined in theusual way using results from 12 concentrations of the compound.

[0634] (b) In vitro Elevation of PDH Activity in Isolated Primary Cells

[0635] This assay determines the ability of compounds to stimulatepyruvate oxidation in primary rat hepatocytes.

[0636] Hepatocytes were isolated by the two-step collagenase digestionprocedure described by Seglen (Methods Cell Biol. (1976) 13, 29-33) andplated out in 6-well culture plates (Falcon Primaria) at 600000 viablecells per well in Dulbecco's Modified Eagles Medium (DMEM, Gibco BRL)containing 10% foetal calf serum (FCS), 10% penicillin/streptomycin(Gibco BRL) and 10% non-essential amino acids (NEAA, Gibco BRL). After 4hours incubation at 37° C. in 5% CO₂, the medium was replaced withMinimum Essential Medium (MEM, Gibco BRL) containing NEAA andpenicillin/streptomycin as above in addition to 10 nM dexamethasone and10 nM insulin.

[0637] The following day cells were washed with phosphate bufferedsaline (PBS) and medium replaced with 1 ml HEPES-buffered Krebs solution(25 mM HEPES, 0.15M sodium chloride, 25 mM sodium hydrogen carbonate, 5mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium sulphate, 1mM potassium dihydrogen phosphate) containing the compound to be testedat the required concentration in 0.1% DMSO. Control wells contained 0.1%DMSO only and a maximum response was determined using a 10 μM treatmentof a known active compound. After a preincubation period of 40 minutesat 37° C. in 5% CO₂, cells were pulsed with sodium pyruvate to a finalconcentration of 0.5 mM (containing 1-¹⁴C sodium pyruvate (Amershamproduct CFA85) 0.18 Ci/mmole) for 12 minutes. The medium was thenremoved and transferred to a tube which was immediately sealed with abung containing a suspended centre well. Absorbent within the centrewell was saturated with 50% phenylethylamine, and CO₂ in the mediumreleased by the addition of 0.2 μl 60% (w/v) perchloric acid (PCA).Released ¹⁴CO₂ trapped in the absorbent was determined by liquidscintillation counting. The ED₅₀ for a test compound was determined inthe usual way using results from 7 concentrations of the compound.

[0638] (c) In vivo Elevation of PDH Activity

[0639] The capacity of compounds to increase the activity of PDH inrelevant tissues of rats may be measured using the test describedhereinafter. Typically an increase in the proportion of PDH in itsactive, nonphosphorylated form may be detected in muscle, heart, liverand adipose tissue after a single administration of an active compound.This may be expected to lead to a decrease in blood glucose afterrepeated administration of the compound. For example a singleadministration of DCA, a compound known to activate PDH by inhibition ofPDH kinase (Whitehouse, Cooper and Randle (1974) Biochem. J. 141,761-774) 150 mg/kg, intraperitoneally, increased the proportion of PDHin its active form (Vary et al. (1988) Circ. Shock 24, 3-18) and afterrepeated administration resulted in a significant decrease in plasmaglucose (Evans and Stacpoole (1982) Biochem. Pharmacol.31, 1295-1300).

[0640] Groups of rats (weight range 140-180 g) are treated with a singledose or multiple doses of the compound of interest by oral gavage in anappropriate vehicle. A control group of rats is treated with vehicleonly. At a fixed time after the final administration of compound,animals are terminally anaesthetised, tissues are removed and frozen inliquid nitrogen. For determination of PDH activity, muscle samples aredisrupted under liquid nitrogen prior to homogenisation by onethirty-second burst in a Polytron homogenizer in 4 volumes of a buffercontaining 40 mM potassium phosphate pH 7.0, 5 mM EDTA, 2 mM DTT, 1%Triton X-100, 10 mM sodium pyruvate, 10 μM phenylmethylsulphonylchloride (PMSF) and2 μg/ml each of leupeptin, pepstain A and aprotinin.Extracts are centrifuged before assay. A portion of the extract istreated with PDH phosphatase prepared from pig hearts by the method ofSiess and Wieland (Eur. J. Biochem (1972) 26, 96): 20 μl extract, 40 μlphosphatase (1:20 dilution), in a final volume of 125 μl containing 25mM magnesium chloride, 1 mM calcium chloride. The activity of theuntreated sample is compared with the activity of the dephosphorylatedextract thus prepared. PDH activity is assayed by the method of Stansbieet al., (Biochem. J. (1976)154, 225). 50 μl Extract is incubated with0.75 mM NAD, 0.2 mM CoA, 1.5 mM thiamine pyrophosphate (TPP) and 1.5 mMsodium pyruvate in the presence of 20 μg/ml p-(p-amino-phenylazo)benzene sulphonic acid (AABS) and 50 mU/ml arylamine transferase (AAT)in a buffer containing 100 mM tris(hydroxymethyl)aminomethane, 0.5 mMEDTA, 50 mM sodium fluoride, 5 mM 2-mercaptoethanol and 1 mM magnesiumchloride pH 7.8. AAT is prepared from pigeon livers by the method ofTabor et al. (J. Biol. Chem. (1953) 204, 127). The rate of acetyl CoAformation is determined by the rate of reduction of AABS which isindicated by a decrease in optical density at 460 nm.

[0641] Liver samples are prepared by an essentially similar method,except that sodium pyruvate is excluded from the extraction buffer andadded to the phosphatase incubation to a final concentration of 5 mM.

[0642] Treatment of an animal with an active compound results in anincrease in the activity of PDH complex in tissues. This is indicated byan increase in the amount of active PDH (determined by the activity ofuntreated extract as a percentage of the total PDH activity in the sameextract after treatment with phosphatase).

[0643] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a compound of the formula(I) as defined hereinbefore or a pharmaceutically acceptable saltthereof, in association with a pharmaceutically acceptable excipient orcarrier.

[0644] According to an additional aspect of the invention there isprovided a pharmaceutical composition which comprises a compound of theformula (I′) as defined hereinbefore or a pharmaceutically acceptablesalt thereof, in association with a pharmaceutically acceptableexcipient or carrier.

[0645] The composition may be in a form suitable for oraladministration, for example as a tablet or capsule, for parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion) for example as a sterile solution, suspensionor emulsion, for topical administration for example as an ointment orcream or for rectal administration for example as a suppository. Ingeneral the above compositions may be prepared in a conventional mannerusing conventional excipients.

[0646] The compositions of the present invention are advantageouslypresented in unit dosage form. The compound will normally beadministered to a warm-blooded animal at a unit dose within the range5-5000 mg per square metre body area of the animal, i.e. approximately0.1-100 mg/kg. A unit dose in the range, for example, 1-100 mg/kg,preferably 1-50 mg/kg is envisaged and this normally provides atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example 1-250 mg of active ingredient.

[0647] According to a further aspect of the present invention there isprovided a compound of the formula (I) or a pharmaceutically acceptablesalt thereof as defined hereinbefore for use in a method of treatment ofthe human or animal body by therapy.

[0648] According to an additional aspect of the present invention thereis provided a compound of the formula (I′) or a pharmaceuticallyacceptable salt thereof as defined hereinbefore for use in a method oftreatment of the human or animal body by therapy.

[0649] We have found that compounds of the present invention elevate PDHactivity and are therefore of interest for their blood glucose-loweringeffects.

[0650] A further feature of the present invention is a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as amedicament, conveniently a compound of formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament forproducing an elevation of PDH activity in a warm-blooded animal such asa human being.

[0651] A further feature of the present invention is a compound offormula (I′), or a pharmaceutically acceptable salt thereof, for use asa medicament, conveniently a compound of formula (I′), or apharmaceutically acceptable salt thereof, for use as a medicament forproducing an elevation of PDH activity in a warm-blooded animal such asa human being.

[0652] Thus according to a further aspect of the invention there isprovided the use of a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for use inthe production of an elevation of PDH activity in a warm-blooded animalsuch as a human being.

[0653] Thus according to an additional aspect of the invention there isprovided the use of a compound of the formula (I′), or apharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the production of an elevation of PDH activity ina warm-blooded animal such as a human being.

[0654] According to a further feature of the invention there is provideda method for producing an elevation of PDH activity in a warm-bloodedanimal, such as a human being, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof as definedhereinbefore.

[0655] As stated above the size of the dose required for the therapeuticor prophylactic treatment of a particular disease state will necessarilybe varied depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

[0656] The elevation of PDH activity described herein may be applied asa sole therapy or may involve, in addition to the subject of the presentinvention, one or more other substances and/or treatments. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate administration of the individual components of the treatment.For example in the treatment of diabetes mellitus chemotherapy mayinclude the following main categories of treatment:

[0657] i) insulin;

[0658] ii) insulin secretagogue agents designed to stimulate insulinsecretion (for example glibenclamide, tolbutamide, othersulphonylureas);

[0659] iii) oral hypoglycaemic agents such as metformin,thiazolidinediones;

[0660] iv) agents designed to reduce the absorption of glucose from theintestine (for example acarbose);

[0661] v) agents designed to treat complications of prolongedhyperglycaemia;

[0662] vi) other agents used to treat lactic acidaemia;

[0663] vii) inhibitors of fatty acid oxidation;

[0664] viii) lipid lowering agents;

[0665] ix) agents used to treat coronary heart disease and peripheralvascular disease such as aspirin, pentoxifylline, cilostazol; and/or

[0666] x) thiamine.

[0667] As stated above the compounds defined in the present inventionare of interest for their ability to elevate the activity of PDH. Suchcompounds of the invention may therefore be useful in a range of diseasestates including diabetes mellitus, peripheral vascular disease,(including intermittent claudication), cardiac failure and certaincardiac myopathies, myocardial ischaemia, cerebral ischaemia andreperfusion, muscle weakness, hyperlipidaemias, Alzheimer's disease andatherosclerosis.

[0668] In addition to their use in therapeutic medicine, the compoundsof formula (I) and their pharmaceutically acceptable salts are alsouseful as pharmacological tools in the development and standardisationof in vitro and in vivo test systems for the evaluation of the effectsof elevators of PDH activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

[0669] It is to be understood that where the term “ether” is usedanywhere in this specification it refers to diethyl ether.

[0670] The invention will now be illustrated by the followingnon-limiting examples in which, unless stated otherwise:

[0671] (i) temperatures are given in degrees Celsius (° C.); operationswere carried out at room or ambient temperature, that is, at atemperature in the range of 18-25° C. and under an atmosphere of aninert gas such as argon;

[0672] (ii) organic solutions were dried over anhydrous magnesiumsulphate; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with abath temperature of up to 60° C.;

[0673] (iii) chromatography means flash chromatography on silica gel;thin layer chromatography (TLC) was carried out on silica gel plates;where a silica Mega Bond Elut column is referred to, this means a columncontaining 10 g or 20 g of silica of 40 micron particle size, the silicabeing contained in a 60 ml disposable syringe and supported by a porousdisc, obtained from Varian. Harbor City, Calif., USA under the name“Mega Bond Elut SI”; “Mega Bond Elut” is a trademark;

[0674] (iv) where a Chem Elut column is referred to, this means a“Hydromatrix” extraction cartridge for adsorption of aqueous material,i.e. a polypropylene tube containing a special grade of flux-calcined,high purity, inert diatomaceous earth, pre-buffered to pH 4.5 or 9.0,incorporating a phase-separation filtering material, used according tothe manufacturers instructions, obtained from Varian, Harbor City,Calif., USA under the name of “Extube, Chem Elut”; “Extube” is aregistered trademark of International Sorbent Technology Limited;

[0675] (v) where an ISOLUTE column is referred to, this means an “ionexchange” extraction cartridge for adsorption of basic or acid material,i.e. a polypropylene tube containing a special grade of ion exchangesorbent, high purity, surface to pH˜7, incorporating a phase-separationfiltering material, used according to the manufacturers instructions,obtained from Varian, Harbor City, Calif., USA under the name of“Extube, Chem Elut, ISOLUTE”; “Extube” is a registered trademark ofInternational Sorbent Technology Limited;

[0676] (vi) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

[0677] (vii) melting points are uncorrected and (dec) indicatesdecomposition; the melting points given are those obtained for thematerials prepared as described; polymorphism may result in isolation ofmaterials with different melting points in some preparations;

[0678] (viii) final products had satisfactory proton nuclear magneticresonance (NMR) spectra and/or mass spectral data;

[0679] (ix) yields are given for illustration only and are notnecessarily those which can be obtained by diligent process development;preparations were repeated if more material was required;

[0680] (x) where given, NMR data is in the form of delta values formajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHzusing perdeuterio dimethyl sulphoxide (DMSO-δ₆) as solvent unlessotherwise indicated, other solvents (where indicated in the text)include deuterated chloroform —CDCl₃ and deuterated acetic acid AcOH-δ₄;coupling constants (J) are given in Hz; Ar designates an aromatic protonwhen such an assignment is made;

[0681] (xi) chemical symbols have their usual meanings; SI units andsymbols are used;

[0682] (xii) reduced pressures are given as absolute pressures inPascals (Pa); elevated pressures are given as gauge pressures in bars;

[0683] (xiii) solvent ratios are given in volume : volume (v/v) terms;

[0684] (xiv) mass spectra (MS) were run with an electron energy of 70electron volts in the chemical ionisation (CI) mode using a directexposure probe; where indicated ionisation was effected by electronimpact (El), fast atom bombardment (FAB) or electrospray (ESP); valuesfor m/z are given; generally, only ions which indicate the parent massare reported and unless otherwise stated the value quoted is (M—H)⁻;

[0685] (xv) Oxone is a Trademark of E. I. du Pont de Nemours & Co.,Inc., and refers to potassium peroxymonosulphate;

[0686] xvi) The following abbreviations are used: EA elemental analysis;DMF N,N-dimethylformamide; DMA N,N-dimethylacetamide; TFAtrifluoroacetic acid; NMP N-methylpyrrolidin-2-one SM starting material;DCM dichloromethane; and THF tetrahydrofuran;

[0687] (xvii) HPLC Methods referred to in the text are as follows:Methods a and b LC/MS method: Machine Model HP1100 Column 4.6 mm × 10 cmHichrom RPB 100A Wavelength 254 nm Injection 10 μl Flow rate 1 ml/minuteSolvent A 0.1% Formic Acid/Water Solvent B 0.1% FormicAcid/Acetonitrile. Time/minutes A% B% Solvent gradient for Method a:0.00 95 5 1.50 95 5 7.50 5 95 9.00 5 95 Solvent gradient for Method b:0.00 95 5 1.50 95 5 11.50 5 95 13.50 5 95 Method c: Column 7.5 mm × 25cm Dynamax −60A C18 83-201-C Flow rate 1 ml/minute Time/minutes % MeCNin water + 0.1% TFA Solvent gradient for Method c: 0 10 2 10 32 90Method d: Column 4.5 mm × 10 cm HIRPB Flow rate   1 ml/min SolventGradient 50-70% MeOH in water + 0.1% TFA over 10 minutes (xviii) where(R) or (S) stereochemistry is quoted at the beginning of a name, unlessfurther clarified, it is to be understood that the indicatedstereochemistry refers to the A-B-C*(R²)(R³)(R⁴) centre as depicted informula (I).

EXAMPLE 1

[0688](R)—N-[2-Chloro4-(2-methylsulphanylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0689] Sodium methanethiolate (49.5 mg) was added to a solution of(R)—N-[2-chloro-4-(2-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Method 63) (0.15 g) in NMP (1.5 ml) and the mixture was heated at 120°C. for 18 hours then cooled. Saturated aqueous ammonium chloridesolution (15 ml) was added and the mixture was extracted with ethylacetate (2×50 ml). The organic extracts were combined, washed with brineand dried. Volatile material was removed by evaporation and the residuewas purified by chromatography on a silica gel Mega Bond Elut columneluting with 0-20% ethyl acetate/hexane to give the title compound (0.10g) as a solid. NMR: (CDCl₃): 1.75 (s, 3H), 2.4 (s, 3H), 3.6 (brs, 1H),7.3 (t, 1H), 7.35 (t, H), 7.55 (m, 1H), 7.9 (dd, 1H), 8.05 (d, 1H) 8.25(dd. 1H), 8.6 (d, 1H), 9.25 (brs, 1H); MS (ESP⁻): 452.

EXAMPLES 2-12

[0690] Following the procedure of Example 1 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR (CDCl₃) MS SM 2 (R)-N-[2-Chloro-4-(4-methyl- 1.75 (s, 3H), 2.5 (s,3H), 3.7 (s, 452 Meth sulphanylphenylsulphonyl) 1H), 7.28 (d, 2H), 7.8(d, 2H), 69 phenyl]-2-hydroxy-2-methyl- 7.83 (dd, 1H), 7.98 (d, 1H), 8.6(d, 3,3,3-trifluoropropanamide 1H), 9.25 (brs, 1H) 3(R)-N-{2-Chloro-4-[2-(ethyl- 1.25 (t, 3H), 1.75 (s, 3H), 2.90 (q, 466Meth sulphanyl)phenylsulphonyl] 2H), 3.75 (s, 1H), 7.30-7.35 (m, 63phenyl}-2-hydroxy-2-methyl- 2H), 7.45-7.50 (m, 1H), 7.90-7.953,3,3-trifluoropropanamide (m, 1H), 8.10 (d, 1H), 8.25 (d, 1H), 8.60 (d,1H), 9.30 (s, 1H) 4 (R)-N-[2-Chloro-4-(3-methyl- 1.75 (s, 3H), 2.52 (s,3H), 3.5 (s, 452 Meth sulphanylphenylsulphonyl) 1H), 7.37-7.41 (m, 2H),7.6-7.65 70 phenyl]-2-hydroxy-2-methyl- (m, 1H), 7.75 (s, 1H), 7.85 (d,3,3,3-trifluoropropanamide 1H), 8.0 (d, 1H), 8.60 (d, 1H), 9.2 (s, 1H) 5(R)-N-[2-Chloro-4-(4-methyl- 1.72 (s, 3H), 2.5 (s, 3H), 4.45 436 Methsulphanylphenylsulphinyl) (2xbrs, 1H), 7.3 (d, 2H), 7.49 (m, 75phenyl]-2-hydroxy-2-methyl- 1H), 7.5 (d, 2H), 7.7 (m, 1H), 8.53,3,3-trifluoropropanamide (2xd, 1H), 9.2 (2xbrs, 1H) 6(R)-N-{2-Chloro-4-[4-(iso- 1.35 (d, 6H), 1.7 (s, 3H), 3.5 (m, 480 Methpropylsulphanyl)phenyl- 1H), 5.35 (s, 1H), 7.35 (d, 2H), 69sulphonylphenyl}-2-hydroxy- 7.75-7.85 (m, 3H), 8.0 (dd, 1H),2-methyl-3,3,3- 8.6 (d, 1H), 9.5 (brs, 1H) trifluoropropanamide 7(R)-N-[2-Chloro-4-(4-ethyl- 1.35 (t, 3H), 1.7 (s, 3H), 3.0 (q, 466 Methsulphanylphenylsulphonyl) 2H), 5.2 (s, 1H), 7.3 (m, 1H), 7.7- 69phenyl]-2-hydroxy-2-methyl- 8.0 (m, 5H), 8.6 (d, 1H), 9.45 (brs,3,3,3-trifluoropropanamide 1H) 8 (R)-N-[2-Chloro-4-(3-chloro-4- 1.75 (s,3H), 2.5 (s, 3H), 3.80 (s, 488 Meth methylsulphanylphenyl 1H), 7.2 (d,1H), 7.75 (dd, 1H). (M + H)⁺ 72 sulphonyl)phenyl]-2-hydroxy- 7.8-7.85(m, 2H), 7.95 (d, 1H), 2-methyl-3,3,3- 8.6 (d, 1H), 9.30 (brs, 1H)trifluoropropanamide 9 (R)-N-[2-Chloro-4-(3-fluoro-4- 1.75 (s, 3H), 2.5(s, 3H), 3.6 (s, 470 Meth methylsulphanylphenyl 1H), 7.25 (m, 1H), 7.5(dd, 1H), 66 sulphonyl)phenyl]-2-hydroxy- 7.65 (d, 1H), 7.85 (dd, 1H),7.95 2-methyl-3,3,3- (d, 1H), 8.6 (d, 1H), 9.25 (brs, 1H)trifluoropropanamide 10  (R)-N-[2-Fluoro-4-(4-ethyl- 450 Methsulphanylphenylsulphonyl) 71 phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide  11¹  (R)-N-[2-Methylsulphanyl-4- R.f. =0.37; 1:1 iso-hexane:Ethyl Meth (2-methylsulphanylphenyl acetate 64sulphonyl)phenyl]-2-hydroxy- 2-methyl-3,3,3- trifluoropropanamide 12 (R)-N-[2-Fluoro-4-(2-methyl- 436 Meth sulphanylphenylsulphonyl) 64phenyl]-2-hydroxy-2-methyl- 3,3,3-trifluoropropanamide

EXAMPLE 13

[0691](R)—N-{2-Chloro-4-[2-(methylsulphinyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0692] m-Chloroperoxybenzoic acid (50%, 0.293 g) was added to a solutionof(R)—N-[2-chloro-4-(2-methylsulphanylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 1) (0.384 g) in DCM (40 ml). The mixture was stirred at ambienttemperature for 6 hours then washed with saturated aqueous sodiumhydrogen carbonate solution (3×100 ml), water (100 ml) and brine andthen dried. Volatile material was removed by evaporation and the residuewas purified by chromatography on a silica gel Mega Bond Elut columneluting with 50-70% ethyl acetate/hexane to give the title compound(0.26 g) as a solid. Mp 118-120° C.; NMR (CDCl₃): 1.70 (s, 3H), 3.0 (m,3H), 4.85 (brs, 1H), 7.75 (t, 1H), 7.85 (m, 2H), 8.0 (m, 1H), 8.15 (d,1H), 8.3 (d, 1H), 8.65 (dd, 1H), 9.40 (brs. 1H); MS (ESP⁻): 468; EA:found: C, 44.3; H, 3.7; N, 2.6%; C₁₇H₁₅ClF₃NO₅S₂.0.125 C₄H₈O₂.0.3 C₄H₁₀Orequires: C, 44.64; H, 3.81; N, 2.78%.

EXAMPLES 14-15

[0693] Following the procedure of Example 13 and using the appropriatestarting materials the following compound was prepared. Ex Compound NMR(CDCl₃) MS SM 14¹ (R)-N-[2-Chloro-4-(4- 1.72 (s, 3H), 3.02 (s, 3H), 3.9(brs, 468 Ex 87 mesylphenylsulphinyl)- 1H), 7.58 (m, 1H), 7.72 (m, 1H),phenyl]-2-hydroxy-2-methyl- 7.82 (d, 2H), 8.05 (d, 2H), 8.583,3,3-trifluoropropanamide (m, 1H), 9.2 (brs, 1H) 15²N-(2-Fluoro-4-phenyl- 1.35 (s, 6H), 6.0 (brs, 1H), 7.5- 320  Ex 205sulphinylphenyl)-2-hydroxy- 7.56 (m, 4H), 7.64 (d, 1H), 7.72-methylpropanamide (m, 2H), 8.18 (t, 1H), 9.4 (brs, 1H)

EXAMPLE 16

[0694](R)—N-[2-Chloro-4-(2-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0695] m-Chloroperoxybenzoic acid (50%, 2.39 g) was added to a solutionof(R)—N-[2-chloro-4-(2-methylsulphanylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 1) (1.3 g) in DCM (100 ml) and the mixture was stirred atambient temperature for 3 hours. A further portion ofm-chloroperoxybenzoic acid (0.82 g) was added and the mixture wasstirred for 24 hours and then washed with saturated aqueous sodiumhydrogen carbonate solution (3×70 ml), water (50 ml) and brine and thendried. Volatile material was removed by evaporation and the residue waspurified by flash chromatography eluting with 50% ethyl acetate/hexaneto give the title compound (0.606 g) as a solid. Mp 114-116° C.; NMR(CDCl₃): 1.75 (s, 3H), 3.45 (s, 3H), 3.65 (brs, 1H), 7.8-7.95 (m, 3H),8.10 (d, 1H), 8.35 (dd, 1H), 8.55 (dd, 1H), 8.60 (d, 1H) 9.30 (brs, 1H);MS (ESP⁻): 484; EA: found: C, 42.3; H, 3.3; N, 2.6%; C₁₇H₁₅ClF₃NO₆S₂requires: C, 42.02; H, 3.11; N, 2.88%.

EXAMPLES 17-53

[0696] Following the procedure of Example 16 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM 17 (R)-N-{2-Chloro-4-[2-(ethyl- (CDCl₃) 1.25 (t, 3H), 1.75 (s,498 Ex 3 sulphonyl)phenylsulphonyl] 3H), 3.70 (q, 2H), 3.75 (brs,phenyl}-2-hydroxy-2-methyl-3,3,3- 1H). 7.80-7.95 (m, 3H), 8.10trifluoropropanamide (s, 1H), 8.30 (d, 1H), 8.60 (d, 2H), 9.25 (s, 1H)18 (R)-N-{2-Chloro-4-[4-(2- (CDCl₃ + trace of DMSO-δ₆) 514 Exhydroxyethylsulphonyl)phenyl- 1.59 (s, 3H), 3.29 (t, 2H), 3.85 284sulphonyl]phenyl}-2-hydroxy-2- (m, 2H), 4.0 (m, 1H), 7.3 (s,methyl-3,3,3-trifluoropropanamide 1H), 7.78 (dd, 1H), 7.9 (d, 1H), 8.0(s, 4H), 8.6 (d, 1H), 9.72 (brs, 1H) 19 (R)-N-{2-Chloro-4-[2-(2-(CDCl₃ + AcOH-δ₄) 1.71 (s, 514 Ex hydroxyethylsulphonyl)phenyl- 3H), 4.0(t, 2H), 4.08 (t, 2H), 290 sulphonyl]phenyl}-2-hydroxy-2- 7.8-7.95 (m,3H), 8.08 (d, 1H), methyl-3,3,3-trifluoropropanamide 8.31 (d, 1H), 8.52(d, 1H), 8.62 (d, 1H) 20 (R)-N-[2-Chloro-4-(3-mesyl- (CDCl₃) 1.75 (s,3H), 3.08 (s, 484 Ex 4 phenylsulphonyl)phenyl]-2- 3H), 3.5 (s, 1H), 7.75(t, 1H), hydroxy-2-methyl-3,3,3- 7.88 (dd, 1H), 8.01 (d, 1H),trifluoropropanamide 8.17 (dd, 1H), 8.48 (s, 1H), 8.67 (d, 1H), 9.3(brs, 1H) 21 (R)-N-[2-Chloro-4-(4-benzoyl- 1.6 (s, 3H), 7.6 (m, 3H), 8.0525 Ex aminophenylsulphonyl)phenyl]-2- (m, 8H), 8.1 (s, 1H), 8.3 (d, 337hydroxy-2-methyl-3,3,3- 1H), 9.9 (s, 1H), 10.6 (s, 1H)trifluoropropanamide 22 (R)-N-{2-Chloro-4-[4-(t-butyl- 1.2 (s, 9H), 1.6(s, 3H), 7.9 (s, 505 Ex carbonylamino)phenylsulphonyl] 5H), 8.1 (s, 1H),8.3 (d, 1H), 338 phenyl}-2-hydroxy-2-methyl-3,3,3- 9.6 (s, 1H)trifluoropropanamide 23 (R)-N-{2-Chloro-4-[4-(4-chloro- 1.6 (s, 3H), 7.6(d, 2H), 8.0 (m, 559 Ex benzoylamino)phenylsulphonyl] 8H), 8.1 (s, 1H),8.3 (d, 1H), 339 phenyl}-2-hydroxy-2-methyl-3,3,3- 9.9 (s, 1H), 10.7 (s,1H) trifluoropropanamide 24 (R)-N-{2-Chloro-4-[4-(2-methoxy- 1.6 (s,3H), 3.3 (s, 3H), 4.0 (s. 493 Ex acetylamino)phenylsulphonyl] 2H), 7.9(m, 6H), 8.1 (s, 1H), 340 phenyl}-2-hydroxy-2-methyl-3,3,3- 8.3 (d, 1H),10.2 (s, 1H) trifluoropropanamide 25 (R)-N-{2-Chloro-4-[4-(1-oxy- 1.6(s, 3H), 8.0 (m, 8H), 8.1 (s, 542 Ex pyridin-3-ylcarbonylamino)phenyl-1H), 8.3 (d, 1H), 8.4 (d, 2H), 341 sulphonyl]phenyl}-2-hydroxy-2- 9.9(s, 1H), 10.75 (s, 1H) methyl-3,3,3-trifluoropropanamide 26(R)-N-[2-Chloro-4-(4-ureido- 1.6 (s, 3H), 4.0 (d, 1H), 6.1 (s, 464 Exphenylsulphonyl)phenyl]-2- 2H), 7.6 (d, 2H), 7.8 (d, 2H), 174hydroxy-2-methyl-3,3,3- 7.9 (d, 1H), 8.0 (s, 1H), 8.3 (d,trifluoropropanamide 1H), 9.0 (s, 1H), 9.8 (s, 1H) 27(R)-N-[2-Chloro-4-(2-ureido- 1.6 (s, 3H), 6.7 (s, 2H), 7.2 (t, 464 Exphenylsulphonyl)phenyl]-2- 1H), 7.6 (m, 2H), 8.0 (m, 3H), 175hydroxy-2-methyl-3,3,3- 8.2 (d, 2H), 8.3 (s, 1H), 9.9 (s,trifluoropropanamide 1H) 28 (R)-N-[2-Chloro-4-(2-mesylamino- 1.6 (s,3H), 3.3 (s, 3H), 7.4 (t, 499 Ex phenylsulphonyl)phenyl]-2- 1H), 7.5 (d,1H), 7.7 (t, 1H), 342 hydroxy-2-methyl-3,3,3- 8.0 (m, 4H), 8.3 (d, 1H),9.1 (s, trifluoropropanamide 1H), 9.9 (s, 1H) 29(R)-N-[2-Chloro-4-(2-acetylamino- 1.6 (s, 3H), 2.0 (s, 3H), 7.4 (m, 463Ex phenylsulphonyl)phenyl]-2- 1H), 7.7 (d, 2H), 7.9 (d, 1H), 343hydroxy-2-methyl-3,3,3- 8.0 (d, 2H), 8.1 (d, 1H), 8.3 (d,trifluoropropanamide 1H), 9.4 (s, 1H), 9.9 (s, 1H) 30(R)-N-[2-Chloro-4-(N-methyl-4- 1.6 (s, 3H), 3.0 (s, 3H), 3.3 (s, 513 Exmesylaminophenylsulphonyl) 3H), 7.6 (d, 2H), 8.0 (m, 4H), 263phenyl]-2-hydroxy-2-methyl-3,3,3- 8.1 (s, 1H), 8.3 (d, 1H), 9.9 (s,trifluoropropanamide 1H) 31 (R)-N-[2-Chloro-4-(4-mesylamino- 1.6 (s,3H), 3.1 (s, 3H), 7.4 (d, 499 Ex phenylsulphonyl)phenyl]-2- 2H), 7.9 (m,3H), 8.0 (s, 1H), 344 hydroxy-2-methyl-3,3,3- 8.1 (s, 1H), 8.3 (d, 1H),9.9 (s, trifluoropropanamide 1H), 10.48 (s, 1H) 32(R)-N-{2-Chloro-4-[4-(phenyl- 1.6 (s, 3H), 7.2 (d, 2H), 7.6 (m, 561 Exsulphonylamino)phenylsulphonyl] 3H), 7.8 (m, 5H), 8.0 (d, 2H), 345phenyl}-2-hydroxy-2-methyl-3,3,3- 8.2 (d, 1H), 9.9 (s, 1H), 11.0 (s,trifluoropropanamide 1H) 33 (R)-N-[2-Chloro-4-(4-ethenyl- 1.6 (s, 3H),6.1 (d, 1H), 6.2 (d, 511 Ex sulphonylaminophenylsulphonyl) 1H), 6.9 (m,1H), 7.3 (d, 2H), 346 phenyl]-2-hydroxy-2-methyl-3,3,3- 7.9 (d, 3H), 8.0(s, 1H), 8.1 (s, trifluoropropanamide 1H), 8.3 (d, 1H), 9.9 (s, 1H),10.75 (s, 1H) 34 (R)-N-[2-Chloro-4-(3-mesylamino- 1.6 (s, 3H), 3.0 (s,3H), 7.5 (d, 499 Ex phenylsulphonyl)phenyl]-2- 1H), 7.6 (t, 1H), 7.7 (m,2H), 347 hydroxy-2-methyl-3,3,3- 8.0 (m, 3H), 8.3 (d, 1H), 9.9 (s,trifluoropropanamide 1H), 10.2 (s, 1H) 35(R)-N-[2-Fluoro-4-(4-mesylamino- 1.6 (s, 3H), 3.2 (s, 3H), 7.3 (d, 483Ex phenylsulphonyl)phenyl]-2- 2H), 7.7 (m, 2H), 7.9 (m, 3H), 348hydroxy-2-methyl-3,3,3- 8.0 (t, 1H), 9.9 (s, 1H), 10.5 (s,trifluoropropanamide 1H) 36 (R)-N-[2-Fluoro-4-(4-acetylamino- 1.6 (s,3H), 2.1 (s, 3H), 7.7 (m, 447 Ex phenylsulphonyl)phenyl]-2- 4H), 7.8 (m,3H), 8.0 (t, 1H), 349 hydroxy-2-methyl-3,3,3- 9.9 (s, 1H), 10.35 (s, 1H)trifluoropropanamide 37 (R)-N-{2-Chloro-4-[4-(2-chloro- 1.6 (s, 3H), 4.3(s, 2H), 7.8 (d, 497 Ex acetylamino)phenylsulphonyl] 2H), 8.0 (m, 4H),8.1 (s, 1H), 177 phenyl}-2-hydroxy-2-methyl-3,3,3- 8.3 (d, 1H), 9.9 (s,1H), 10.72 trifluoropropanamide (s, 1H) 38(R)-N-(2-Chloro-4-{4-[2-(N′-oxy- 1.6 (s, 3H), 3.2 (s, 6H), 4.0 (s, 522Ex N′,N′-dimethylamino)acetylamino] 2H), 7.7 (d, 2H), 7.9 (m, 4H), 353phenylsulphonyl}phenyl)-2- 8.0 (s, 1H), 8.3 (d, 1H)hydroxy-2-methyl-3,3,3- trifluoropropanamide 39(R)-N-{2-Chloro-4-[4-(3-t- 1.2 (s, 9H), 1.6 (s, 3H), 6.2 (s, 520 Exbutylureido)phenylsulphonyl] 1H), 7.5 (d, 2H), 7.8 (d, 2H), 179phenyl}-2-hydroxy-2-methyl-3,3,3- 7.9 (d, 1H), 8.0 (d, 2H), 8.2 (d,trifluoropropanamide 1H), 8.8 (s, 1H), 9.9 (s, 1H) 40(R)-N-{2-Chloro-4-[4-(3-phenyl- 1.6 (s, 3H), 7.0 (t, 1H), 7.3 (t, 540 Exureido)phenylsulphonyl]phenyl}-2- 2H), 7.4 (d, 2H), 7.7 (d, 2H), 180hydroxy-2-methyl-3,3,3- 7.9 (m, 4H), 8.0 (s, 1H), 8.3 (d,trifluoropropanamide 1H), 8.8 (s, 1H), 9.2 (s, 1H), 9.8 (s, 1H) 41(R)-N-[2-Chloro-4-(2,3-H-2-oxo-3- 1.6 (s, 3H), 3.3 (s, 3H), 7.4 (d, 477Ex methylbenzoxazol-6-ylsulphonyl) 1H), 7.9 (m, 3H), 8.1 (s, 1H), 265phenyl]-2-hydroxy-2-methyl-3,3,3- 8.2 (d, 1H), 9.9 (s, 1H)trifluoropropanamide 42 (R)-N-[2-Chloro-4-(2-oxo-1,3- 1.5 (s, 3H), 3.3(d, 6H), 7.3 (d, 490 Ex dimethylbenzimidazolidin-5- 1H), 7.7 (t, 2H),8.0 (t, 2H), 8.1 266 ylsulphonyl)phenyl]-2-hydroxy-2- (s, 1H), 8.2 (d,1H), 9.9 (s, 1H) methyl-3,3,3-trifluoropropanamide 43(R)-N-{2-Chloro-4-[4-(2-oxo- 1.6 (s, 3H), 2.1 (m, 2H), 2.5 (t, 489 Expyrrolidin-1-yl)phenylsulphonyl] 2H), 3.9 (t, 2H), 7.9 (m, 6H), 267phenyl}-2-hydroxy-2-methyl-3,3,3- 8.1 (s, 1H), 8.3 (d, 1H), 9.9 (s,trifluoropropanamide 1H) 44 (R)-N-[2-Chloro-4-(1,2,3,4-H-1,3- 1.6 (s,3H), 3.2 (s, 3H), 3.5 (s, 518 Ex dimethyl-2,4-dioxoquinazolin-6- 3H),7.6 (d, 1H), 8.0 (d, 2H), 268 ylsulphonyl)phenyl]-2-hydroxy-2- 8.2 (s,1H), 8.3 (m, 2H), 8.5 (s, methyl-3,3,3-trifluoropropanamide 1H), 9.9 (s,1H) 45 (R)-N-{2-Chloro-4-(4,5-diphenyl- (CDCl₃) 1.75 (s, 3H), 3.8 (brs,551 Ex 2-oxazolylsulphonyl)phenyl}-2- 1H), 7.3-7.45 (m, 6H), 7.5-7.65(M + H)⁺ 272 hydroxy-2-methyl-3,3,3- (m, 4H), 8.1 (dd, 1H), 8.2 (d,trifluoropropanamide 1H), 8.75 (d, 1H), 9.4 (brs, 1H) 46(R)-N-{2-Chloro-4-(1-ethyltetrazol- (CDCl₃) 1.65 (t, 3H), 1.75 (s, 428Ex 5-ylsulphonyl)phenyl}-2-hydroxy- 3H), 3.7 (brs, 1H), 4.85 (q, (M +H)⁺ 273 2-methyl-3,3,3- 2H), 8.05 (dd, 1H), 8.2 (d, 1H),trifluoropropanamide 8.8 (d, 1H), 9.5 (brs, 1H) 47(R)-N-{2-Chloro-4-(4-iso-propyl- (CDCl₃) 1.55 (d, 6H), 1.75 (s, 457 Ex4,5-dihydro-1H-1,2,4-triazol-5-one- 3H), 3.8 (brs, 1H), 4.8 (m, 1H),(M + H)⁺ 274 3-ylsulphonyl)phenyl}-2-hydroxy- 7.9 (dd, 1H), 8.05 (d,1H), 8.8 2-methyl-3,3,3- (d, 1H), 9.45 (brs, 1H), 10.2trifluoropropanamide (brs, 1H) 48 (R)-N-{2-Chloro-4-[3-fluoro-4-(2- 1.6(s, 3H), 3.55-3.65 (m, 2H), 532 Ex hydroxyethylsulphonyl)- 3.65-3.8 (m,2H), 4.80 (m 1H), 311 phenylsulphonyl]phenyl}-2- 8.00-8.15 (m, 4H),8.15-8.3 (m, hydroxy-2-methyl-3,3,3- 2H), 8.35 (d, 1H), 9.95 (brs,trifluoropropanamide 1H) 49 (R)-N-[2-Chloro-4-(3-chloro-4- (CDCl₃) 1.75(s, 3H), 3.25 (s, 518 Ex 8 methylsulphonylphenylsulphonyl) 3H), 3.45(brs, 1H), 7.9 (dd, phenyl]-2-hydroxy-2-methyl-3,3,3- 1H), 7.95-8.1 (m,2H), 8.1 (d, trifluoropropanamide 1H), 8.3 (d, 1H), 8.56 (d, 1H), 9.3(brs, 1H) 50 (R)-N-[2-Chloro-4-(3-fluoro-4- (CDCl₃) 1.75 (s, 3H), 3.2(s, 502 Ex 9 methylsulphonylphenylsulphonyl) 3H), 3.4 (s, 1H), 7.8 (dd,1H), phenyl]-2-hydroxy-2-methyl-3,3,3- 7.9 (dd, 2H), 8.0 (d, 1H), 8.1-trifluoropropanamide 8.15 (m, 1H), 8.7 (d, 1H), 9.3 (brs, 1H) 51(R)-N-{2-Chloro-4-(3-t-butoxy- (CDCl₃): 1.55 (s, 9H), 1.78 (s, 487 Excarbonylaminopropylsulphonyl) 3H), 1.86-1.97 (m, 2H), 3.13 (t, 405phenyl}-2-hydroxy-2-methyl-3,3,3- 2H), 3.21-3.26 (m, 2H), 3.86trifluoropropanamide (s, 1H), 4.65 (t, 1H), 7.80-7.82 (m, 1H), 8.04 (s,1H), 8.68 (d, 1H), 9.34 (s, 1H) 52 (R)-N-{2-Chloro-4-(2H- 1.6 (s, 3H),7.1 (d, 1H), 7.4 (s, 462 Ex benzimidazole-2-one-5-yl- 1H), 7.6 (d, 1H),7.9 (d, 1H), 269 sulphonyl)phenyl}-2-hydroxy-2- 8.0 (s, 1H), 8.2 (d,1H), 11.0 (s, methyl-3,3,3-trifluoropropanamide 1H), 11.2 (s, 1H) 53(R)-N-{2-Chloro-4-(4-acetyl- 1.6 (s, 3H), 2.6 (s, 3H), 8.0 (s, 448 Exphenylsulphonyl)phenyl}-2- 2H), 8.1 (s, 3H), 8.2 (s, 1H), 270hydroxy-2-methyl-3,3,3- 8.3 (d, 1H), 9.9 (s, 1H) trifluoropropanamide

EXAMPLE 54

[0697](R)—N-{2-Chloro-4-[2-(2-hydroxyethylamino)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0698] Ethanolamine (0.014 ml) was added to a solution of(R)—N-[2-chloro-4-(2-fluoro-phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Method 63) (0.10 g) in NMP (1.5 ml) and the solution was heated at 120°C. for 18 hours then cooled. Saturated aqueous ammonium chloridesolution (10 ml) was added and the mixture was extracted with ethylacetate (2×20 ml). The organic extracts were combined, washed with brineand dried. Volatile material was removed by evaporation and the residuewas purified by chromatography on a silica gel Mega Bond Elut columneluting with 0-50% ethyl acetateihexane to give the title compound(0.074 g) as a solid. Mp 68-70° C.; NMR (CDCl₃): 1.75 (s, 3H), 3.3 (q,2H), 3.90 (m, 2H), 3.95 (brs, 1H), 6.50 (brt, 1H), 6.70 (d, 1H) 6.80 (m,1H), 7.4 (m, 1H), 7.85 (m, 2H), 8.00 (d, 1H), 8.55 (d, 1H), 9.25 (brs,1H); MS (ESP⁻): 465; EA: found: C, 46.6; H, 4.0; N, 5.8%;C₁₈H₁₈ClF₃N₂O₅S requires: C, 46.31; H, 3.89; N, 6.00%.

EXAMPLES 55-85

[0699] Following the procedure of Example 54 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS 55 (R)-N-{2-Chloro-4-[4-(3- 1.6 (s, 3H), 1.66 (m, 2H), 3.1 (m,479 hydroxypropylamino)phenyl- 2H), 3.46 (m, 2H), 4.45 (t, 1H),sulphonyl]phenyl}-2-hydroxy-2- 6.64 (d, 2H), 6.74 (t, 1H), 7.6 (d,methyl-3,3,3-trifluoropropanamide 2H), 7.82 (dd, 1H), 7.98 (d, 1H), 8.2(d, 1H), 9.8 (brs, 1H) 56 (R)-N-{2-Chloro-4-[4-(2- 1.09 (d, 3H), 1.6 (s,3H), 3.0 (m, 479 hydroxypropylamino)phenyl- 2H), 3.77 (m, 1H), 4.72 (d,1H), sulphonyl]phenyl}-2-hydroxy-2- 6.7 (d, 2H), 6.74 (t, 1H), 7.59 (d,methyl-3,3,3-trifluoropropanamide 2H), 7.85 (dd, 1H), 7.96 (d, 1H), 8.22(d, 1H), 9.8 (brs, 1H) 57 (R)-N-{2-Chloro-4-[4-(2-acetamido- 1.6 (s,3H), 1.79 (s, 3H), 3.15 (m, 506 ethylamino)phenylsulphonyl]phenyl}- 4H),6.69 (d, 2H), 6.82 (m, 1H), 2-hydroxy-2-methyl-3,3,3- 7.63 (d, 2H), 7.85(dd, 1H), 7.93 trifluoropropanamide (m, 1H), 8.0 (d, 1H), 8.2 (d, 1H),9.8 (brs, 1H) 58 (R)-N-(2-Chloro-4-{4-[2-(2- 1.6 (s, 3H), 3.25 (m, 2H),3.4-3.6 511 hydroxyethoxy)ethylamino]phenyl- (m, 6H), 4.59 (m, 1H), 6.7(d, 2H), (M + H)⁺ sulphonyl}phenyl)-2-hydroxy-2- 6.79 (t, 1H), 7.68 (d,2H), 7.88 (dd, methyl-3,3,3-trifluoropropanamide 1H), 7.99 (d, 1H), 8.22(d, 1H), 9.8 (brs, 1H) 59 (R)-N-{2-Chloro-4-[4-(4-hydroxy- 1.4-1.63 (m,7H), 3.04 (m, 2H), 3.4 495 butylamino)phenylsulphonyl]phenyl}- (m, 2H),4.38 (t, 1H), 6.62 (d, 2H), (M + H)⁺ 2-hydroxy-2-methyl-3,3,3- 6.76 (t,1H), 7.6 (d, 2H), 7.82 (dd, trifluoropropanamide 1H), 7.46 (d, 1H), 8.22(d, 1H), 9.78 (brs, 1H) 60 (R)-N-{2-Chloro-4-[4-(2,2-dimethyl- 0.84 (s,6H), 1.59 (s, 3H), 2.97 (d, 509 3-hydroxypropylamino)phenyl- 2H), 3.19(d, 2H), 4.59 (m, 1H), (M + H)⁺ sulphonyl]phenyl}-2-hydroxy-2- 6.52 (m,1H), 6.72 (d, 2H), 7.59 (d, methyl-3,3,3-trifluoropropanamide 2H), 7.83(dd, 1H), 7.94 (d, 1H), 8.21 (d, 1H), 9.8 (brs, 1H) 61(R)-N-[2-Chloro-4-[4-(2,3- 1.59 (s, 3H), 2.99 (m, 1H), 3.2 (m, 495dihydroxypropylamino)phenyl- 1H), 3.3 (m, partially obscured bysulphonyl]phenyl}-2-hydroxy-2- water peak), 3.59 (m, 1H), 4.63 (t,methyl-3,3,3-trifluoropropanamide 1H), 4.83 (d, 1H), 6.7 (d, 2H), 6.78(t, 1H), 7.6 (d, 2H), 7.84 (dd, 1H), 7.99 (d, 1H), 8.2 (d, 1H), 9.85(brs, 1H) 62 (R)-N-{2-Chloro-4-[4-(1,3- 1.45 (s, 3H), 3.3 (brs, 5H), 4.5(brs, 495 dihydroxyprop-2-ylamino)phenyl- 2H), 6.3 (d, 1H), 6.59 (d,2H), 7.47 sulphonyl]phenyl}-2-hydroxy-2- (d, 2H), 7.7 (dd, 1H), 7.83 (d,1H), methyl-3,3,3-trifluoropropanamide 8.08 (d, 1H), 9.7 (brs, 1H) 63(R)-N-{2-Fluoro-4-[4-(2-hydroxy- (CDCl₃) 1.69 (s, 3H), 2.84 (t, 1H), 449ethylamino)phenylsulphonyl]phenyl}- 3.27-3.33 (m, 2H), 3.8-3.86 (m,2-hydroxy-2-methyl-3,3,3- 2H), 5.9 (t, 1H), 6.59 (d, 1H), 6.75trifluoropropanamide (s, 1H), 7.60-7.68 (m, 4H), 8.53 (t, 1H), 9.27 (s,1H) 64 (R)-N-{2-Chloro-4-[2-(3-hydroxy- (CDCl₃) 1.75 (s, 3H), 1.85-1.95491 pyrrolidin-1-yl)phenylsulphonyl] (m, 1H), 2.1-2.25 (m, 1H), 2.9 (q,phenyl}-2-hydroxy-2-methyl-3,3,3- 1H), 3.05-3.2 (m, 3H), 3.75 (d,trifluoropropanamide 1H), 4.48 (brs, 1H), 7.27-7.32 (m, 2H), 7.55 (t,1H), 7.8 (t, 1H), 8.07 (dd, 1H), 8.14 (d, 1H), 8.5 (d, 1H), 9.2 (brs,1H) 65 (R)-N-{2-Chloro-4-[2-(N,N- (CDCl₃) 1.75 (s, 3H), 2.3 (s, 6H), 492dimethylaminoethylamino)phenyl- 2.6 (t, 2H), 3.14 (q, 2H), 6.5 (brt,sulphonyl]phenyl}-2-hydroxy-2- 1H), 6.6 (d, 1H), 6.72 (t, 1H), 7.35methyl-3,3,3-trifluoropropanamide (t, 1H), 7.86 (t, 2H), 8.0 (d, 1H),8.55 (d, 1H), 9.3 (brs, 1H) 66 (R)-N-{2-Chloro-4-[2-morpholino (CDCl₃)1.76 (s, 3H), 2.8 (brs, 4H), 491 phenylsulphonyl]phenyl}-2-hydroxy- 3.6(brs, 1H), 3.74 (brs, 4H), 7.3 2-methyl-3,3,3-trifluoropropanamide (d,1H), 7.4 (t, 1H), 7.62 (t, 1H), 7.75 (d, 1H), 8.1 (s, 1H), 8.27 (d, 1H),8.52 (d, 1H), 9.2 (brs, 1H) 67 (R)-N-{2-Chloro-4-[2-(4-methyl- (CDCl₃)1.75 (s, 3H), 2.32 (s, 3H), 504 piperazin-1-yl)phenylsulphonyl] 2.5(brs, 4H), 2.83 (t, 4H), 7.3 (d, phenyl}-2-hydroxy-2-methyl-3,3,3- 1H),7.37 (t, 1H), 7.6 (t, 1H), 7.72 trifluoropropanamide (dd, 1H), 8.1 (s,1H), 8.25 (d, 1H), 8.53 (d, 1H), 9.4 (brs, 1H) 68(R)-N-[2-Chloro-4-(4-benzyl- 1.74 (s, 3H), 4.35 (s, 2H), 6.58- 511aminophenylsulphonyl)phenyl]-2- 6.63 (m, 2H), 7.26-7.39 (m, 5H),hydroxy-2-methyl-3,3,3- 7.62-7.70 (m, 2H), 7.72-7.80 (m,trifluoropropanamide 1H), 7.94 (s, 1H), 8.50-8.57 (m, 1H), 9.18 (brs,1H) 69 (R)-N-[2-Chloro-4-(3-chloro-4-(2- (CDCl₃) 1.75 (s, 3H), 3.4 (q,2H), 501 hydroxyethylamino)phenylsulphonyl) 3.5 (s, 1H), 3.85 (q, 2H),5.25 (m, (M + H)⁺ phenyl]-2-hydroxy-2-methyl-3,3,3- 1H), 6.65 (d, 1H),7.65 (dd, 1H), trifluoropropanamide 7.75-7.85 (m, 2H), 7.95 (d, 1H),8.55 (d, 1H), 9.15 (brs, 1H) 70 (R)-N-[2-Chloro-4-(3-fluoro-4-(2-(CDCl₃) 1.75 (s, 3H), 3.35 (q, 2H), 485hydroxyethylamino)phenylsulphonyl) 3.65 (s, 1H), 3.9 (t, 2H), 4.8 (m,(M + H)⁺ phenyl]-2-hydroxy-2-methyl-3,3,3- 1H), 6.7 (t, 1H), 7.5 (dd,1H), 7.60 trifluoropropanamide (dd, 1H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.55(d, 1H), 9.2 (brs, 1H) 71 (R)-N-{2-Chloro-4-[4-(2- (CDCl₃ + DMSO-δ₆) 1.6(s, 3H), 465 hydroxyethylamino)phenylsulphonyl] 3.2 (q, 2H), 3.7 (m,3H), 5.15 (t, phenyl}-2-hydroxy-2-methyl-3,3,3- 1H), 6.51 (d, 2H), 7.14(s, 1H), trifluoropropanamide 7.58 (d, 2H), 7.68 (d, 1H), 7.83 (d, 1H),8.49 (d, 1H), 9.64 (brs, 1H) 72 (R)-N-{2-Chloro-4-[4-(2- (CDCl₃) 1.76(s, 3H), 3.29-3.28 481 methoxyethylamino)phenylsulphonyl] (m, 2H), 3.39(s, 3H), 3.6 (t, 2H), (M + H)⁺ phenyl}-2-hydroxy-2-methyl-3,3,3- 3.75(s, 1H), 4.64 (t, 1H), 6.59 (d, trifluoropropanamide 2H), 7.69 (d, 2H),7.8 (dd, 1H), 7.94 (d, 1H), 8.54 (d, 1H), 9.2 (brs, 1H) 73(R)-N-(2-Chloro-4-[4-morpholino (CDCl₃) 1.73 (s, 3H), 3.25-3.34 493phenylsulphonyl]phenyl}-2-hydroxy- (m, 4H), 3.8-3.9 (m, 5H), 6.99 (d,(M + H)⁺ 2-methyl-3,3,3-trifluoropropanamide 2H), 7.72-7.86 (m, 3H),7.96 (d, 1H), 8.57 (d, 1H), 9.29 (brs, 1H) 74(R)-N-{2-Chloro-4-[4-(2-methyl- (CDCl₃) 1.74 (s, 3H), 2.1 (s, 3H), 497sulphanylethylamino)phenyl- 2.76 (t, 2H), 3.36 (q, 2H), 3.7 (s, (M + H)⁺sulphonyl]phenyl}-2-hydroxy-2- 1H), 4.72 (t, 1H), 6.6 (d, 2H), 7.7methyl-3,3,3-trifluoropropanamide (d, 2H), 7.79 (dd, 1H), 7.94 (d, 1H),8.54 (d, 1H), 9.21 (brs, 1H) 75 (R)-N-{2-Chloro-4-[4-(2- (CDCl₃) 1.78(s, 3H), 3.66 (brs, 501 furylmethylamino)phenylsulphonyl] 1H), 4.34 (d,2H), 4.63 (t, 1H), phenyl}-2-hydroxy-2-methyl-3,3,3- 6.22 (m, 1H), 6.35(m, 1H), 6.66 trifluoropropanamide (d, 2H), 7.36 (d, 1H), 7.69 (d, 2H),7.8 (dd, 1H), 7.93 (d, 1H), 8.55 (d, 1H), 9.2 (brs, 1H) 76(R)-N-{2-Chloro-4-[4-({1- (CDCl₃) 1.1 (t, 3H), 1.73 (s, 3H), 532ethylpyrrolidin-2-yl}methylamino) 3.4 (t, 1H), 5.4 (brs, 1H), 6.59 (d,phenylsulphonyl]phenyl}-2-hydroxy- 2H), 7.68 (d, 2H), 7.7-7.8 (m, 1H),2-methyl-3,3,3-trifluoropropanamide 7.93 (d, 1H), 8.54 (d, 1H), 9.36(brs, 1H)  77¹ (R)-N-{2-Chloro-4-[4-(iso-propyl- 1.12 (s, 3H), 1.14 (s,3H), 1.6 (s, 463 amino)phenylsulphonyl]phenyl}-2- 3H), 3.61 (m, 1H),6.62 (m, 3H), hydroxy-2-methyl-3,3,3- 7.6 (d, 2H), 7.83 (dd, 1H), 7.97(d, trifluoropropanamide 1H), 8.20 (d, 1H), 9.86 (brs, 1H)  78¹(R)-N-{2-Chloro-4-[4-(cyclopropyl- 0.18 (m, 2H), 0.46 (m, 2H), 0.99 475methylamino)phenylsulphonyl] (m, 1H), 1.58 (s, 3H), 2.9 (m, 2H),phenyl}-2-hydroxy-2-methyl-3,3,3- 6.65 (d, 2H), 6.90 (t, 1H), 7.60 (d,trifluoropropanamide 2H), 7.83 (dd, 1H), 7.95 (m, 2H), 8.19 (d, 1H),9.87 (brs, 1H)  79¹ (R)-N-{2-Chloro-4-[4-(pyrrolidin-1- 1.6 (s, 3H),1.94 (m, 4H), 3.28 (m, 475 yl)phenylsulphonyl]phenyl}-2- 4H), 6.62 (d,2H), 7.7 (d, 2H), 7.85 hydroxy-2-methyl-3,3,3- (dd, 1H), 7.9-8.02 (brs,1H), 7.99 trifluoropropanamide (d, 1H), 8.2 (d, 1H), 9.86 (brs, 1H) 80(R)-N-{2-Chloro-4-[4-(3-hydroxy- 1.68 (s, 3H), 1.99 (m, 1H), 2.08 491pyrrolidin-1-yl)phenylsulphonyl] (m, 1H), 3.2 (d, 1H), 3.37-3.42 (m,phenyl}-2-hydroxy-2-methyl-3,3,3- 2H), 4.47 (brs, 1H), 5.04 (d, 1H),trifluoropropanamide 6.66 (d, 2H), 7.75 (d, 2H), 7.9 (dd, 1H), 8.04 (d,1H), 8.26 (d, 1H), 9.9 (brs, 1H) 81 (R)-N-{2-Chloro-4-[4-(4-hydroxy-1.42 (m, 2H), 1.68 (s, 3H), 1.82 505 piperidin-1-yl)phenylsulphonyl] (m,2H), 3.12 (m, 2H), 3.75 (m, phenyl}-2-hydroxy-2-methyl-3,3,3- 3H), 4.77(d, 1H), 7.08 (d, 2H), trifluoropropanamide 7.79 (d, 2H), 7.9-8.1 (brs),7.94 (dd, 1H), 8.09 (d, 1H), 8.3 (d, 1H), 9.9 (brs, 1H) 82(R)-N-{2-Chloro-4-[4-thiomorpholino 1.59 (s, 3H), 2.6 (m, 4H), 3.78 (m,509 phenylsulphonyl]phenyl}-2-hydroxy- 4H), 7.0 (d, 2H), 7.71 (d, 2H),7.88 (M + H)⁺ 2-methyl-3,3,3-trifluoropropanamide (dd, 1H), 8.0 (brs,1H), 8.02 (d, 1H), 8.25 (d, 1H), 9.87 (brs, 1H) 83(R)-N-{2-Chloro-4-[4-(4-hydroxy- 1.15 (m, 2H), 1.6 (s, 3H), 1.69 (m, 519methylpiperidin-1-yl)phenyl- 2H), 2.82 (m, 2H), 3.27 (m, 2H),sulphonyl]phenyl}-2-hydroxy-2- 3.9 (m, 2H), 4.45 (t, 1H), 7.0 (d,methyl-3,3,3-trifluoropropanamide 2H), 7.69 (d, 2H), 7.89 (dd, 1H), 8.0(d, 1H), 8.22 (d, 1H), 9.85 (brs, 1H) 84 (R)-N-{2-Chloro-4-[4-(3- 1.27(m, 1H), 1.5 (m, 1H), 1.69 (s, 519 hydroxymethylpiperidin-1- 3H), 1.7(m, 3H), 2.76 (m, 2H), yl)phenylsulphonyl]phenyl}-2- 2.94 (m, 1H), 3.89(m, 2H), 4.6 (t, hydroxy-2-methyl-3,3,3- 1H), 7.03 (d, 2H), 7.77 (d,2H), trifluoropropanamide 7.94 (dd, 1H), 8.09 (d, 1H), 8.3 (d, 1H), 9.92(brs, 1H) 85 (R)-N-{2-Chloro-4-[4-(4-{2- 1.15 (m, 2H), 1.6 (s, 3H), 1.69(m, 534 hydroxyethyl}piperazin-1- 2H), 2.82 (m, 2H), 3.27 (m, 2H),yl)phenylsulphonyl]phenyl}-2- 3.9 (m, 2H), 4.45 (t, 1H), 7.0 (d,hydroxy-2-methyl-3,3,3- 2H), 7.69 (d, 2H), 7.89 (dd, 1H),trifluoropropanamide 8.0 (d, 1H), 8.22 (d, 1H), 9.85 (brs, 1H)

EXAMPLE 86

[0700](R)—N-{2-Chloro-4-[4-(methylsulphinyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0701] t-Butylhydroperoxide (0.36 ml of a 3M solution in toluene) wasadded to a solution of(R)—N-{2-chloro-4-[4-(methylsulphanyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 2) (0.247 g) and d-10-camphorsulphonic acid (0.012 g) inchloroform (5 ml) and the mixture was stirred at ambient temperature for64 hours. The reaction mixture was transferred directly to a silica gelMega Bond Elut column and eluted with 0-80% ethyl acetate/hexane to givethe title compound (0.237 g) as a foam. NMR (CDCl₃): 1.74 (s, 3H), 2.74(s, 3H), 4.2 (brs, 1H), 7.79 (d, 2H), 7.89 (dd, 1H), 8.0 (m, 1H), 8.1(d, 2H) 8.65 (d, 1H), 9.38 (brs, 1H); MS (ESP⁻): 468; EA: found: C,43.3; H, 3.1; N, 2.98%; C₁₇H₁₅ClF₃NO₅S₂ requires: C, 43.3; H, 3.1; N,2.8%.

EXAMPLES 87-103

[0702] Following the procedure of Example 86 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR (CDCl₃) MS SM  87¹ (R)-N-{2-Chloro-4-[4-(methyl- 1.72 (s, 3H), 2.76(s, 3H), 5.0 452 Ex sulphinyl)phenylsulphinyl] (brm, 1H), 7.53 (m, 1H),7.7-7.82 189 phenyl}-2-hydroxy-2-methyl- (m, 5H), 8.56 (m, 1H), 9.35(brs, 3,3,3-trifluoropropanamide 1H) 88 (R)-N-{2-Chloro-4-[3-(methyl-1.70 (s, 3H), 2.80 (s, 3H), 5.60 468  Ex 4 sulphinyl)phenylsulphonyl](brs, 1H), 7.70-7.75 (m, 1H), 7.85 phenyl}-2-hydroxy-2-methyl- (d, 2H),8.00 (s, 1H), 8.05 (d, 1H), 3,3,3-trifluoropropanamide 8.20 (s, 1H),8.65 (d, 1H), 9.55 (s, 1H) 89 (R)-N-[2-Chloro-4-(4- (DMSO-δ₆) 1.6 (s,3H), 6.9-7.0 406 Ex hydroxyphenylsulphinyl) (m, 3H), 7.5 (d, 2H), 7.6(dd, 1H), 252 phenyl]-2-hydroxy-2-methyl- 7.8 (s, 1H), 7.9 (s, 1H), 8.1(d, 3,3,3-trifluoropropanamide 1H), 9.8 (s, 1H) 90(R)-N-{2-Chloro-4-[4-(methyl- 1.72 (s, 3H), 2.73 (m, 3H), 4.72 436 Exsulphinyl)phenylsulphanyl] (m, 1H), 7.34 (d, 2H), 7.41 (d, 189phenyl}-2-hydroxy-2-methyl- 1H), 7.5-7.6 (m, 3H), 8.45 (d,3,3,3-trifluoropropanamide 2H), 9.2 (brd, 1H) 91(R)-N-{2-Chloro-4-[4-(2- (CDCl₃ + DMSO-δ₆) 1.58 (s, 3H), 498 Exhydroxyethylsulphinyl)phenyl- 2.84 (m, 1H), 2.98 (m, 1H), 3.75 284sulphonyl]phenyl}-2-hydroxy- (m, 1H), 3.94 (m, 1H), 4.66 (t,2-methyl-3,3,3- 1H), 7.45 (s, 1H), 7.73 (d, 2H), trifluoropropanamide7.76 (dd, 1H), 7.91 (d, 1H), 7.99 (d, 2H), 8.6 (d, 1H), 9.72 (brs, 1H)92 (R)-N-(2-Chloro-4-methyl- 1.77 (s, 3H), 2.74 (s, 3H), 4.7 and 328 Exsulphinylphenyl)-2-hydroxy-2- 4.75 (2xbrs, 1H), 7.49 (t, 1H), 191methyl-3,3,3- 7.74 (d, 1H), 8.59 (m, 1H), 9.3 trifluoropropanamide (brd,1H) 93 (R)-N-(2-Fluoro-4-ethyl- (DMSO-δ₆) 1.09-1.18 (m, 3H), 326 Exsulphinylphenyl)-2-hydroxy-2- 1.68 (s, 3H), 2.65-2.76 (m, 1H), 424methyl-3,3,3- 2.78-2.86 (m, 1H), 4.54 (s, 1H), trifluoropropanamide7.21-7.28 (m, 1H), 7.34-7.43 (m, 1H), 8.42-8.50 (m, 1H), 8.85 (brs, 1H)94 (R)-N-(2-Fluoro-4-methyl- (DMSO-δ₆) 1.68 (s, 3H), 2.65 (s, 312 Exsulphinylphenyl)-2-hydroxy-2- 3H), 4.50 (s, 1H), 7.26-7.32 (m, 196methyl-3,3,3- 1H), 7.42-7.50 (m, 1H), 8.47 (t, trifluoropropanamide 1H),8.85 (s, 1H) 95 (R)-N-[2-Chloro-4-(3- (DMSO-δ₆) 1.44-1.56 (m, 1H), 372Ex hydroxypropylsulphinyl) 1.6 (s, 3H), 1.69-1.78 (m, 1H), 328phenyl]-2-hydroxy-2-methyl- 2.77-2.87 (m, 1H), 2.98-3.08 (m,3,3,3-trifluoropropanamide 1H), 3.43 (t, 2H), 7.65 (d, 1H), 7.81 (s,1H), 7.92 (s, 1H), 8.18 (d, 1H), 9.85 (s, 1H) 96(R)-N-[2-Chloro-4-(cyclo- 1.20-1.26 (m, 6H), 1.76 (s, 3H), 396 Exhexylsulphinyl)phenyl]-2- 1.80-1.86 (m, 4H), 2.52-2.60 (m, 417hydroxy-2-methyl-3,3,3- 1H), 4.60 and 4.89 (2xs, 1H),trifluoropropanamide 7.36-7.44 (m, 1H), 7.57 and 7.68 (2xs, 1H),8.50-8.55 (m, 1H), 9.21 and 9.23 (2xs, 1H) 97(R)-N-[2-Fluoro-4-(4-ethyl- (DMSO-δ₆) 0.98 (t, 3H), 1.56 (s, 466  Ex 10sulphinylphenylsulphonyl) 3H), 2.73-2.81 (m, 1H), 3.02-3.13phenyl]-2-hydroxy-2-methyl- (m, 1H), 7.84-7.86 (m, 2H), 7.94-3,3,3-trifluoropropanamide 8.05 (m, 2H), 8.14 (d, 2H) 98(R)-N-{2-Chloro-4-[3-chloro- 1.75 (s, 3H), 2.55 (t, 1H), 2.85- 532 Ex4-(2-hydroxyethylsulphinyl)- 2.95 (m, 1H), 3.40-3.55 (m, 2H), 310phenylsulphonyl]phenyl}-2- 4.05-4.15 (m, 1H), 7.95 (dd, 1H),hydroxy-2-methyl-3,3,3- 7.95 (d, 1H), 8.00-8.15 (m, 3H),trifluoropropanamide 8.65 (d, 1H), 9.3 (brs, 1H) 99(R)-N-{2-Chloro-4-[3-fluoro-4- (DMSO-δ₆) 1.6 (s, 3H), 2.9-3.0 518 Ex(2-hydroxyethylsulphinyl)- (m, 1H), 3.1-3.23 (m, 1H), 3.65- (M + H)⁺ 311phenylsulphonyl]phenyl}-2- 3.85 (m, 2H), 5.1 (t, 1H), 7.95 (t,hydroxy-2-methyl-3,3,3- 1H), 8.0-8.15 (m, 3H), 8.2 (m,trifluoropropanamide 1H), 8.3 (d, 1H), 9.9 (brs, 1H) 100 (R)-N-[2-Chloro-4-(3-chloro-4- 1.75 (s, 3H), 2.85 (s, 3H), 3.65 504  Ex8 methylsulphinylphenyl- (brs, 1H), 7.9 (m, 1H), 7.95 (s, (M + H)⁺sulphonyl)phenyl]-2-hydroxy- 1H), 8.0-8.1 (m, 2H), 8.15 (d,2-methyl-3,3,3- 1H), 8.65 (d, 1H), 9.3 (brs, 1H) trifluoropropanamide101  (R)-N-[2-Chloro-4-(3-fluoro-4- 1.74 (s, 3H), 2.85 (s, 3H), 3.95 (d,488  Ex 9 methylsulphinylphenyl- 1H), 7.70 (d, 1H), 7.8-8.1 (m, (M + H)⁺sulphonyl)phenyl]-2-hydroxy- 4H), 8.65 (d, 1H), 9.35 (brs, 1H)2-methyl-3,3,3- trifluoropropanamide 102  (R)-N-[2-Chloro-4-(4-N,N-(DMSO-δ₆) 1.0-1.1 (m, 3H), 1.1- 491 Ex diethylcarbamoylphenyl- 1.20 (m,3H), 1.6 (s, 3H), 3.1-3.2 (M + H)⁺ 234 sulphinyl)phenyl]-2-hydroxy- (m,2H), 3.3-3.4 (m, 2H), 7.5 (d, 2-methyl-3,3,3- 2H), 7.7-7.80 (m, 3H),7.85-7.95 trifluoropropanamide (m, 2H), 8.2 (d, 1H), 9.85 (s, 1H) 103 (R)-N-[2-Chloro-4-(4-{3- (DMSO-δ₆) 1.1-1.15 (m, 4H), 1.6 519 Exhydroxypiperidin-1-yl- (s, 3H), 2.9 (s, 1H), 3.5 (s, 1H), (M + H)⁺ 238carbonyl}phenylsulphinyl) 3.7-3.9 (m, 4H), 7.5 (d, 2H), 7.85phenyl]-2-hydroxy-2-methyl- (s, 1H), 7.7-7.9 (m, 3H), 7.95 (s,3,3,3-trifluoropropanamide 1H), 8.2 (d, 1H), 9.8 (s, 1H)

EXAMPLE 104

[0703](R)—N-[4-(4-Acetamidophenylsulphonyl)-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0704] Oxalyl chloride (0.047 ml) was added to a stirred suspension of(R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9)(0.077 g) in DCM (2.5 ml) containing DMF (1 drop). The mixture wasstirred at ambient temperature for 2 hours and was then added to asolution of 4-(4-acetamidophenylsulphonyl)-2-chloroaniline (Method 10)(0.160 g) in DCM (2.5 ml) and stirred a further 2 hours. Ether (50 ml)was added and the mixture was washed with water (2×50 ml) and brine thendried. Volatile material was removed by evaporation and the residue waspurified by chromatography on a silica gel Mega Bond Elut column elutingwith 0-70% ethyl acetate/toluene to give the title compound (0.025 g) asa solid. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.1-7.3 (brm, 1H), 7.8 (d, 2H),7.9 (m, 3H), 7.97-8.05 (brs, 2H), 8.25 (d, 1H), 10.36 (brs, 1H); MS(ESP⁻): 463; EA: found: C, 47.8; H, 3.6; N, 5.4%; C₁₈H₁₆ClF₃N₂O₅S.0.2C₇H₈ requires: C, 48.2; H, 3.7; N, 5.8%.

EXAMPLES 105-112

[0705] Following the procedure of Example 104 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS  105 (R)-N-{2-Chloro-4-[2-(methoxy- 432carbonyl)phenylsulphanyl]phenyl}- 2-hydroxy-2-methyl-3,3,3-trifluoropropanamide  106 (R)-N-{2-Chloro-4-[2-(ethoxy- 1.3 (t, 3H), 1.6(s, 3H), 4.3 (q, 2H), 446 carbonyl)phenylsulphanyl]phenyl}- 6.85 (d,1H), 7.25 (t, 1H), 7.35-7.55 2-hydroxy-2-methyl-3,3,3- (m, 2H), 7.7 (d,1H), 7.9 (dd, 2H), trifluoropropanamide 8.15 (d, 1H), 9.8 (brs, 1H)  107(R)-N-(2-Fluoro-4-phenylsulphanyl- 1.55 (s, 3H), 7.1 (d, 1H), 7.2 (m,1H), 358 phenyl)-2-hydroxy-2-methyl-3,3,3- 7.3-7.5 (m, 5H), 7.6 (s, 1H),7.7 (t, trifluoropropanamide 1H), 9.65 (s, 1H)   108¹N-(2,4-Dimethoxyphenyl)-2- 1.6 (s, 3H), 3.8 (s, 3H), 3.9 (s, 3H), 292hydroxy-2-methyl-3,3,3- 6.55 (dd, 1H), 6.7 (d, 1H), 7.7 (s, 1H),trifluoropropanamide 8.05 (d, 1H), 9.3 (brs, 1H)   109¹N-[4-Chloro-2-(2-chlorobenzoyl) 1.6 (s, 3H), 7.26 (s, 1H), 7.5-7.57 (m,404 phenyl]-2-hydroxy-2-methyl-3,3,3- 1H), 7.6-7.7 (m, 4H), 7.8 (d, 1H),7.9 trifluoropropanamide (brs, 1H), 8.7 (d, 1H), 12.2 (brs, 1H)   110¹N-(2-Methoxy-4-methoxycarbonyl- 1.6 (s, 3H), 3.85 (s, 3H), 4.0 (s, 3H),320 phenyl)-2-hydroxy-2-methyl-3,3,3- 7.6 (s, 1H), 7.65 (d, 1H), 7.93(s, 1H), trifluoropropanamide 8.37 (d, 1H), 9.7 (brs, 1H)   111¹N-[2-Bromo-4-(iso-propyl)phenyl]- 1.2 (d, 6H), 1.6 (s, 3H), 2.9 (m, 1H),352 2-hydroxy-2-methyl-3,3,3- 7.28 (dd, 1H), 7.5 (d, 1H), 7.75 (brs, andtrifluoropropanamide 1H), 7.9 (d, 1H), 9.6 (brs, 1H) 354   112¹N-[2-Chloro-4-(t-butyl)phenyl]-2- 1.25 (s, 9H), 1.6 (s, 3H), 7.4 (dd,1H), 322 hydroxy-2-methyl-3,3,3- 7.5 (d, 1H), 7.7 (brs, 1H), 7.9 (d,1H), trifluoropropanamide 9.6 (brs, 1H)   113¹N-(2-Bromo-4-ethylphenyl)-2- 1.2 (t, 3H), 1.6 (s, 3H), 2.6 (q, 2H), 7.2338 hydroxy-2-methyl-3,3,3- (dd, 1H), 7.5 (d, 1H), 7.7 (brs, 1H), 7.9and trifluoropropanamide (d, 1H), 9.6 (brs, 1H) 340

EXAMPLE 114

[0706]N-(2-Fluoro-4-phenylsulphonylphenyl)-2-hydroxy-2-methylpropanamide

[0707] Hydrogen peroxide (0.45 ml of a 30 wt. % solution in water) wasadded to a solution ofN-(2-fluoro-4-phenylsulphanylphenyl)-2-hydroxy-2-methylpropanamide(Example 205) (0.34 g) in glacial acetic acid (1.1 ml) and the mixturewas stirred and heated at 100° C. for 2 hours then cooled Water (2 ml)was added to the resultant precipitate and the solid was collected,washed further with water (2×5 ml) and dried in vacuo at 60° C. to givethe title compound (0.347 g) as a solid. Mp 155.5-156.5° C.; NMR: 1.34(s, 6H), 6.08 (brs, 1H), 7.56-7.7 (m, 3H), 7.8 (d, 1H), 7.9 (d, 1H),7.96 (d, 2H), 8.31 (t, 1H), 9.5 (s, 1H); MS (ESP⁻): 336; EA: found: C,57.1; H, 4.7; N, 4.1; S, 9.7%; C₁₆H₁₆FNO₄S requires: C, 57.0; H, 4.8; N,4.2; S, 9.5%

EXAMPLES 115-170

[0708] Following the procedure of Example 114, using the appropriatestarting materials, and using extraction followed by chromatography toisolate and purify the product when necessary, the following compoundswere prepared. Ex Compound NMR MS SM 115 (R)-N-{2-Chloro-4-[4-(dimethyl-1.6 (s, 3H), 2.65 (s, 6H), 7.9- 513 Ex aminosulphonyl)phenylsulphonyl]7.95 (d, 3H), 8.0 (dd, 1H), 251 phenyl}-2-hydroxy-2-methyl- 8.2-8.25 (m,3H), 8.35 (d, 3,3,3-trifluoropropanamide 1H), 9.3 (s, 1H) 116(R)-N-[2-Chloro-4-(4- 1.70 (s, 3H), 6.40 (brs, 2H), 485 Exsulphamoylphenylsulphonyl) 7.20 (s, 1H), 7.80 (d, 1H), 254phenyl]-2-hydroxy-2-methyl- 7.95 (s, 1H), 8.00-8.10 (m,3,3,3-trifluoropropanamide 4H), 8.7 (d, 1H), 9.80 (s, 1H) 117(R)-N-{2-Chloro-4-[4- 1.60 (s, 3H), 6.7 (s, 4H), 7.15 527 Ex(guanidinosulphonyl)phenyl- (d, 2H), 7.25 (d, 1H), 7.65- 255sulphonyl]phenyl}-2-hydroxy-2- 7.70 (m, 3H), 7.90 (s, 1H), methyl-3,3,3-8.1 (d, 1H), 9.75 (s, 1H) trifluoropropanamide 118(R)-N-{2-Chloro-4-[4-(pyrrolidin- (CDCl₃) 1.75 (s, 3H), 1.8- 539 Ex1-ylsulphonyl) phenylsulphonyl] 1.85 (m, 4H), 3.2-3.3 (m, 250phenyl}-2-hydroxy-2-methyl- 4H), 3.55 (s, 1H), 7.85 (dd,3,3,3-trifluoropropanamide 1H), 7.95 (d, 2H), 8.05 (d, 1H), 8.1 (d, 2H),8.65 (d, 1H), 9.3 (s, 1H) 119 (R)-N-[2-Chloro-4-(4-hydroxy- 1.6 (s, 3H),6.95 (d, 2H), 7.8 422 Ex phenylsulphonyl)phenyl]-2- (d, 2H), 7.9 (dd,1H), 8.05 252 hydroxy-2-methyl-3,3,3- (dd, 2H), 9.9 (s, 1H), 10.7 (s,trifluoropropanamide 1H) 120 (R)-N-{2-Chloro-4-[4-(ethoxy- 1.4 (t, 3H),1.76 (s, 3H), 3.6 478 Ex carbonyl)phenylsulphonyl] (s, 1H), 4.4 (q, 2H),7.88 (dd, 190 phenyl}-2-hydroxy-2-methyl- 1H), 7.99 (m, 3H), 8.18 (d,3,3,3-trifluoropropanamide 2H), 8.64 (d, 1H), 9.3 (brs, 1H) 121(R)-N-[2-Chloro-4-(4-carboxy- 1.79 (s, 3H), 8.19 (dd, 2H), 450 Exphenylsulphonyl)phenyl]-2- 8.32 (s, 4H), 8.36 (d, 1H), 291hydroxy-2-methyl-3,3,3- 8.52 (d, 1H), 10.1 (brs, 1H),trifluoropropanamide 13.7 (brs, 1H) 122 (R)-N-{2-Chloro-4-[4-(1,1- 1.61(s, 3H), 3.1-3.4 (brs, 567 Ex dioxothiomorpholinocarbonyl) 4H), 3.6(brs, 2H), 4.0 (brs, 300 phenylsulphonyl]phenyl}-2- 2H), 7.73 (d, 2H),8.02 (dd, hydroxy-2-methyl-3,3,3- 1H), 8.09 (d, 2H), 8.2 (d, 1H),trifluoropropanamide 8.32 (d, 1H), 9.9 (brs, 1H) 123(R)-N-[2-Chloro-4-(1-methyl- 1.7 (s, 3H), 4.01 (s, 3H), 7.18 410 Eximidazol-2-ylsulphonyl)phenyl]- (d, 1H), 7.56 (d, 1H), 8.05 2572-hydroxy-2-methyl-3,3,3- (dd, 1H), 8.13 (d, 1H), 8.42trifluoropropanamide (d, 1H), 10.0 (brs, 1H) 124(R)-N-{2-Chloro-4-[4-(1,1-dioxo- 1.6 (s, 3H), 3.45 (m, 2H), 553 Exthiazolidin-3-ylcarbonyl)phenyl- 4.02 (brs, 2H), 4.64 (s, 2H), 301sulphonyl]phenyl}-2-hydroxy-2- 7.74 (d, 2H), 8.02 (dd, 1H),methyl-3,3,3- 8.1 (d, 2H), 8.19 (d, 1H), 8.33 trifluoropropanamide (d,1H), 9.9 (brs, 1H) 125 (R)-N-[2-Chloro-4-(2-carboxy- 1.60 (s, 3H),7.47-7.57 (m, 450 Ex phenylsulphonyl)phenyl]-2- 2H), 7.63-7.68 (m, 1H),7.98 292 hydroxy-2-methyl-3,3,3- (d, 1H), 8.06 (d, 1H), 8.22 (d,trifluoropropanamide 1H), 8.27 (s, 1H), 9.92 (s, 1H) 126(R)-N-(2-Fluoro-4-ethyl- (DMSO-δ₆ + AcOH-δ₄) 1.07 342  Ex 93sulphonylphenyl)-2-hydroxy-2- (t, 3H), 1.81 (s, 3H), 3.17- methyl-3,3,3-3.23 (q, 2H), 7.67-7.75 (m, trifluoropropanamide 2H), 8.15-8.21 (t, 2H)127 (R)-N-(2-Fluoro-4-mesyl-phenyl)- 1.57 (s, 3H), 3.23 (s, 3H), 328 Ex2-hydroxy-2-methyl-3,3,3- 7.73-7.76 (m, 2H), 7.85 (d, 196trifluoropropanamide 1H), 8.03 (d, 1H), 9.92 (s, 1H) 128(R)-N-[2-Chloro-4-(2-hydroxy- 1.60 (s, 3H), 3.5 (t, 2H), 3.65- 374 Exethylsulphonyl)phenyl]-2- 3.71 (m, 2H), 4.84 (t, 1H), 415hydroxy-2-methyl-3,3,3- 7.86-7.89 (m, 1H), 8.05 (s, trifluoropropanamide1H), 8.31 (d, 1H), 9.89 (brs, 1H) 129 (R)-N-[2-Chloro-4-(cyclopropyl-0.11-0.14 (m, 1H), 0.43-0.45 384 Ex methylsulphonyl)phenyl]-2- (m, 1H),0.81-0.87 (m, 1H), 416 hydroxy-2-methyl-3,3,3- 1.61 (s, 3H), 3.32 (d,2H), trifluoropropanamide 7.85-7.90 (m, 1H), 8.01 (m, 1H), 8.34 (d, 1H)130 (R)-N-[2-Chloro-4-(3- 1.61 (s, 3H), 1.64-1.71 (m, 388 Exhydroxypropylsulphonyl)phenyl]- 2H), 3.32-3.43 (m, 4H), 7.87- 3282-hydroxy-2-methyl-3,3,3- 7.90 (m, 1H), 8.03 (s, 1H),trifluoropropanamide 8.34 (d, 1H) 131 (R)-N-[2-Chloro-4-(N-methyl- 1.63(s, 3H), 2.52 (d, 3H), 401 Ex carbamoylmethylsulphonyl) 4.28 (s, 2H),7.83 (d, 1H), 420 phenyl]-2-hydroxy-2-methyl- 8.10-8.13 (m, 1H), 8.29(d, 3,3,3-trifluoropropanamide 1H) 132 (R)-N-[2-Chloro-4-(iso-propyl-1.10-1.13 (d, 6H), 1.60 (s, 372 Ex sulphonyl)phenyl]-2-hydroxy-2- 3H),3.34-3.42 (m, 1H), 7.8- 421 methyl-3,3,3- 7.82 (d, 1H), 8.92 (s, 1H),trifluoropropanamide 8.41 (d, 1H). 133 (R)-N-[2-Chloro-4-(cyclopentyl-1.55-1.60 (m, 7H), 1.76-1.86 398 Ex sulphonyl)phenyl]-2-hydroxy-2- (m,4H), 3.81-3.89 (m, 1H), 422 methyl-3,3,3- 7.86-7.89 (m, 1H), 8.02 (s,trifluoropropanamide 1H), 8.34 (d, 1H). 134(R)-N-[2-Chloro-4-(iso-butyl- 0.97 (s, 6H), 1.61 (s, 3H), 386 Exsulphonyl)phenyl]-2-hydroxy-2- 1.97-2.05 (m, 1H), 3.26-3.34 423methyl-3,3,3- (m, 2H), 7.68-7.92 (m, 1H), trifluoropropanamide 8.05 (s,1H), 8.31 (d, 1H), 9.92 (s, 1H) 135 (R)-N-[2-Chloro-4-(cyclohexyl-1.13-1.26 (m, 6H), 1.61 (s, 412  Ex 96 sulphonyl)phenyl]-2-hydroxy-2-3H), 1.71-1.76 (m, 2H), 1.84- methyl-3,3,3- 1.88 (m, 2H), 3.31-3.35 (m,trifluoropropanamide 1H), 7.80-7.84 (m, 1H), 7.92 (s, 1H), 8.34 (d, 1H)136 N-[2-Fluoro-4-(4-mesylphenyl- 3.26 (s, 3H), 6.42 (t, 2H), 486 Exsulphonyl)phenyl]-2-hydroxy-2- 7.85-7.94 (m, 2H), 8.01 (d, 200difluoromethyl-3,3- 1H), 8.14 (d, 1H), 8.25 (d, difiuoropropanamide 1H)137 (R)-N-{2-Fluoro-4-[4-(2- 1.57 (s, 3H), 3.54 (t, 2H), 498 Exhydroxyethylsulphonyl)phenyl- 3.65-3.71 (m, 2H), 4.66 (t, 309sulphonyl]phenyl}-2-hydroxy-2- 1H), 7.86 (d, 1H), 7.97-8.05methyl-3,3,3- (m, 2H), 8.07 (d, 1H), 8.21 trifluoropropanamide (d, 1H)138 (R)-N-[2-Fluoro-4-(4-ethyl- 1.05-1.10 (t, 3H), 1.55 (s, 482  Ex 97sulphonylphenylsulphonyl) 3H), 3.31-3.39 (q, 2H), 7.87phenyl]-2-hydroxy-2-methyl- (d, 1H), 7.98-8.05 (m, 1H),3,3,3-trifluoropropanamide 8.11 (d, 2H), 8.24 (d, 2H) 139(R)-N-{2-Fluoro-4-[4-(N- 1.57 (s, 3H), 2.5 (d, 3H), 4.34 525 Exmethylcarbamoylmethyl (s, 2H), 7.86 (d, 1H), 8.0-8.02 308sulphonyl)phenylsulphonyl] (m, 1H), 8.07-8.13 (m, 3H),phenyl}-2-hydroxy-2-methyl- 8.23 (d, 2H) 3,3,3-trifluoropropanamide 140(R)-N-[2-Bromo-4-(4-mesyl- 1.6 (s, 3H), 3.27 (s, 3H), 528 Exphenylsulphonyl)phenyl]-2-hydroxy-2- 8.02-8.08 (m, 2H), 8.15 (d, 201methyl-3,3,3- 2H), 8.26 (d, 2H), 8.33 (s, trifluoropropanamide 1H), 8.36(s, 1H), 9.91 (s, 1H) 141 (R)-N-[2-Chloro-4-(N,N- 1.68 (s, 3H), 2.85 (s,3H), 415 Ex dimethylcarbamoylmethyl- 3.05 (s, 3H), 4.72 (s, 2H), 402sulphonyl)phenyl]-2-hydroxy-2- 7.93 (d, 2H), 8.08 (s, 1H), methyl-3,3,3-8.44 (d, 1H) trifluoropropanamide 142 (R)-N-[2-Chloro-4-(methoxy- 1.62(s, 3H), 3.6 (s, 3H), 4.74 402 Ex carbonylmethylsulphonyl) (s, 2H), 7.9(d, 2H), 8.07 (s, 403 phenyl]-2-hydroxy-2-methyl- 1H), 8.33 (d, 1H)3,3,3-trifluoropropanamide 143 (R)-N-[2-Mesyl-4-(2-mesyl- 1.6 (s, 3H),3.28 (s, 3H), 3.5 528  Ex 11 phenylsulphonyl)phenyl]-2- (s, 3H),8.02-8.05 (m, 2H), hydroxy-2-methyl-3,3,3- 8.18-8.21 (m, 2H), 8.39 (s,trifluoropropanamide 1H), 8.5-8.53 (d, 1H), 8.62 (d, 1H), 11.1 (brs, 1H)144 (R)-N-(2-Chloro-4-ethyl- 1.07 (t, 3H), 1.6 (s, 3H), 3.32 358 Exsulphonylphenyl)-2-hydroxy-2- (q, 2H), 7.85 (d, 1H), 8.01 (s, 327methyl-3,3,3- 1H), 8.32 (d, 1H) trifluoropropanamide 145(R)-N-{2-Chloro-4-[4-(N- 1.60 (s, 3H), 3.3 (3H, s), 4.35 541 Exmethylcarbamoylmethyl- (s, 2H), 8.0-8.40 (m, 7H), 288sulphonyl)phenylsulphonyl] 9.95 (bs, 1H) phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide 146 (R)-N-[2-Chloro-4-(4- 0.15 (q, 2H), 0.55(q, 2H), 524 Ex cyclopropylmethylsulphonyl- 0.9-1.00 (m, 1H), 1.75 (s,287 phenylsulphonyl)-phenyl]-2- 3H), 3.05 (d, 2H), 3.65 (s,hydroxy-2-methyl-3,3,3- 1H), 7.9 (dd, 1H), 8. (dd, 1H),trifluoropropanamide 8.05-8.15 (m, 4H), 8.65 (d, 1H), 9.35 (brs, 1H) 147(R)-N-[2-Chloro-4-(4- 1.25 (t, 3H), 1.75 (s, 3H), 3.1 498  Ex 7ethylsulphonylphenylsulphonyl) (q, 2H), 3.5 (s, 1H), 7.9 (dd,phenyl]-2-hydroxy-2-methyl- 1H), 8.0-8.15 (m, 5H), 8.653,3,3-trifluoropropanamide (d, 1H), 9.3 (brs, 1H) 148(R)-N-{2-Chloro-4-[4-(iso- 1.3 (d, 6H), 1.75 (s, 3H), 3.2 512  Ex 6propylsulphonyl)phenyl- (m, 1H), 3.95 (s, 1H), 7.9 (dd,sulphonyl]phenyl}-2-hydroxy-2- 1H), 8.05 (m, 3H), 8.1 (dd, methyl-3,3,3-2H), 8.7 (dd, 1H), 9.4 (brs trifluoropropanamide 1H).  149¹N-(2-Chloro-4-phenylsulphonyl- 6.86 (s, 1H), 7.5-7.75 (m, 376 and See¹    phenyl)dichloroacetamide 3H), 7.9-8.03 (m, 4H), 10.47 378 (brs, 1H) 150¹ N-(2-Chloro-4-phenylsulphonyl- 1.2 (s, 9H), 7.6 (t, 2H), 7.7 (t,350 See¹     phenyl)-2,2-dimethyl- 1H), 7.84-7.92 (m, 2H), 8.0propanamide (d, 2H), 8.05 (d, 1H), 9.1 (brs, 1H)  151¹N-(2-Chloro-4-phenylsulphonyl- 0.8 (m, 4H), 2.1 (m, 1H), 7.6- 334 See¹    phenyl)cyclopropylcarboxamide 7.72 (m, 3H), 7.85 (dd, 1H), 7.95 (d,2H), 8.03 (s, 1H), 8.1 (d, 1H), 9.9 (brs, 1H)  152¹N-(2-Chloro-4-phenylsulphonyl- 1.6 (d, 3H), 4.95 (q, 1H), 7.6 356 andSee¹     phenyl)-2-chloropropanamide (t, 2H), 7.7 (t, 1H), 7.9 (dd, 3581H), 8.0 (d, 2H), 8.05-8.1 (m, 2H), 10.09 (brs, 1H)  153¹N-(2-Chloro-4-phenylsulphonyl- 1.1 (d, 6H), 2.8 (m, 1H), 7.6 336 See¹    phenyl)-2-methylpropanamide (t, 2H), 7.7 (t, 1H), 7.85 (dd, 1H),7.95 (d, 2H), 8.0-8.1 (m, 2H), 9.6 (s, 1H) 154(R)-N-[2-Fluoro-4-(2-mesyl- 1.55 (s, 3H), 3.5 (s, 3H), 468  Ex 12phenylsulphonyl)phenyl]-2- 7.73-7.78 (m, 2H), 7.85 (dd,hydroxy-2-methyl-3,3,3- 1H), 7.98 (d, 1H), 8.0-8.06 trifluoropropanamide(m, 2H), 8.2 (m, 1H), 8.5 (m, 1H), 9.9 (brs, 1H) 155(R)-N-[2-Fluoro-4-(4-mesyl- 1.6 (s, 3H), 3.3 (s, 3H), 7.78 468 Exphenylsulphonyl)phenyl]-2- (s, 1H), 7.9 (d, 1H), 7.95-8.1 194hydroxy-2-methyl-3,3,3- (m, 2H), 8.15 (d, 2H), 8.25 trifluoropropanamide(d, 2H), 9.85 (s, 1H) 156 (R)-N-{2-Chloro-4-[2-(N,N- 1.06 (m, 3H), 1.25(m, 3H), 505 Ex diethylcarbamoyl)phenyl 1.59 (s, 3H), 3.08 (m, 2H), 232sulphonyl]phenyl}-2-hydroxy-2- 3.39 (m, 1H), 3.67 (m, 1H), methyl-3,3,3-7.41 (d, 1H), 7.66 (t, 1H), trifluoropropanamide 7.78 (t, 1H), 7.98 (d,1H), 8.16 (m, 2H), 8.27 (d, 1H), 9.90 (brs, 1H) 157(R)-N-[2-Chloro-4-(2,3- 1.60 (s, 3H), 3.15-3.23 (m, 404 Exdihydroxypropyl)sulphonyl- 2H), 3.36-3.44 (m, 2H), 3.36- 425phenyl]-2-hydroxy-2-methyl- 3.44 (m, 2H), 3.81-3.89 (m,3,3,3-trifluoropropanamide 1H), 4.86 (t, 1H), 4.94 (d, 1H), 7.86-7.89(m, 1H), 8.02 (s, 1H), 8.31 (d, 1H), 9.89 (s, 1H) 158(R)-N-[2-Chloro-4-(2-hydroxy- 1.11 (d, 3H), 1.60 (s, 3H), 388 Expropyl)sulphonylphenyl]-2- 3.39-3.44 (m, 2H), 4.00-4.05 426hydroxy-2-methyl-3,3,3- (m, 1H), 4.84 (d, 1H), 7.86-trifluoropropanamide 7.89 (m, 1H), 8.02 (s, 1H). 8.31 (d, 1H), 9.89 (s,1H) 159 (R)-N-[2-Chloro-4-t-butyl- 1.26 (s, 9H), 1.63 (s, 3H), 386 Exsulphonylphenyl]-2-hydroxy-2- 7.81-7.84 (m, 1H), 7.89 (s, 427methyl-3,3,3- 1H), 8.39 (d, 1H) trifluoropropanamide 160(R)-N-[2-Chloro-4-(4-{3- (CDCl₃) 1.75 (s, 3H), 2.1-2.2 480 Ex hydroxy-(m, 2H), 3.8-3.9 (m, 1H), 397 propoxy}phenylsulphonyl)phenyl]- 4.05-4.2(m, 2H), 4.2-4.25 2-hydroxy-2-methyl-3,3,3- (m, 1H), 4.65 (s, 1H), 7.0(d, trifluoropropanamide 2H), 7.7-7.85 (m, 3H), 7.9 (s, 1H), 8.6 (d,2H), 9.4 (s, 1H) 161 (R)-N-[2-Chloro-4-(4- 1.6 (s, 3H), 4.55 (s, 2H),7.1- 481 Ex {carbamoylmethoxy}phenyl- 7.2 (m, 2H), 7.35 (s, 1H), 7.5(M + H)⁺ 399 sulphonyl)phenyl]-2-hydroxy-2- (s, 1H), 7.85-7.95 (m, 3H),methyl-3,3,3- 8.0 (s, 1H), 8.1 (s, 1H), 8.2- trifluoropropanamide 8.3(m, 1H), 9.85 (s, 1H) 162 (R)-N-[2-Chloro-4-(4-{N,N- (CDCl₃) 1.75 (s,3H), 3.0 (s, 507 Ex dimethylcarbamoylmethoxy} 3H), 3.1 (s, 3H), 4.75 (s,2H), 400 phenylsulphonyl)phenyl]-2- 6.9 (d, 1H), 7.0 (d, 1H), 7.8-hydroxy-2-methyl-3,3,3- 7.9 (m, 3H), 8.0 (s, 1H), 8.6trifluoropropanamide (d, 2H), 9.3 (s, 1H) 163(R)-N-(2-Chloro-4-{4-[2-(N-oxy- 1.6 (s, 3H), 3.1 (d, 2H), 3.2- 580 Exmorpholino)ethylaminocarbonyl] 3.3 (m, 2H), 3.3-3.4 (m, 2H), (M + H)⁺237 phenylsulphonyl}phenyl)-2- 3.7 (d, 2H), 3.8 (d, 2H), 4.1-hydroxy-2-methyl-3,3,3- 4.2 (m, 2H), 7.9-8.0 (m, 5H),trifluoropropanamide 8.1-8.2 (m, 3H), 8.3 (d, 1H), 10.6 (s, 1H) 164(R)-N-[2-Chloro-4-(4-{3- 1.3-1.5 (2H, m), 1.6 (s, 3H), 535 Exhydroxypiperidin-1-ylcarbonyl} 1.7-1.9 (m, 2H), 2.8-3.0 (m, (M + H)⁺ 238phenyl-sulphonyl)phenyl]-2- 2H), 3.4-3.6 (m, 2H), 3.6-3.7hydroxy-2-methyl-3,3,3- (m, 1H), 4.1 (d, 1H), 7.6 (d,trifluoropropanamide 2H), 8.0-8.1 (m, 4H), 8.2 (s, 1H), 8.3 (d, 1H), 9.9(s, 1H) 165 (R)-N-[2-Fluoro-4-(4- 3.33 (s, 3H), 7.72-7.77 (m, 522 Exmesylphenylsulphonyl)phenyl]-2- 1H), 7.86-7.91 (m, 1H), 8.02 413hydroxy-2-trifluoromethyl-3,3,3- (d, 1H), 8.16 (d, 2H), 8.27 (d,trifluoropropanamide 2H), 9.91 (s, 1H), 10.6 (s, 1H) 166(R)-N-[2-Chloro-4-(2- 0.80 (t, 3H), 1.28-1.33 (m, 402 Exhydroxybutylsulphonyl)phenyl}- 1H), 1.41-1.50 (m, 1H), 1.61 4082-hydroxy-2-methyl-3,3,3- (s, 3H), 3.40 (d, 2H), 3.78-trifluoropropanamide 3.80 (m, 1H), 4.80 (d, 1H), 7.86-7.89 (m, 1H), 8.02(s, 1H), 8.29 (d, 1H) 167 (R)-N-{2-Chloro-4-(2-hydroxy-2- 1.25 (s, 6H),1.61 (s, 3H), 402 Ex methylpropylsulphonyl) phenyl}- 3.47 (s, 2H),7.86-7.89 (m, 409 2-hydroxy-2-methyl-3,3,3- 1H), 8.01 (s, 1H), 8.29 (d,trifluoropropanamide 1H) 168 (R)-N-{2-Chloro-4-propyl- 0.90 (t, 3H),1.26-1.35 (m, 372 Ex sulphonylphenyl}-2-hydroxy-2- 2H), 1.61 (s, 3H),3.32-3.38 410 methyl-3,3,3- (m, 2H), 7.86-7.89 (m, 1H),trifluoropropanamide 8.02 (s, 1H), 8.32 (d, 1H), 9.88 (s, 1H) 169(R)-N-{2-Chloro-4-(butyl- 0.82 (t, 3H), 1.26-1.35 (m, 386 Exsulphonyl)phenyl}-2-hydroxy-2- 2H), 1.45-1.55 (m, 2H), 1.61 411methyl-3,3,3- (s, 3H), 3.31-3.41 (m, 2H), trifluoropropanamide 7.86-7.90(m, 1H), 8.02 (s, 1H), 8.32 (d, 1H) 170 (R)-N-{2-Chloro-4-(3-carboxy-1.58 (s, 3H), 7.76 (t, 1H), 450 Ex phenylsulphonyl)phenyl}-2- 8.03 (d,2H), 8.22 (m, 3H), 293 hydroxy-2-methyl-3,3,3- 8.3 (d, 1H), 8.4 (s, 1H),9.88 trifluoropropanamide (s, 1H)

EXAMPLE 171

[0709]N-[2-Chloro-4-(4-acetamidophenylsulthonyl)phenyl]-2-hydroxy-2-methylpropanamide

[0710] A solution of lithium hydroxide monohydrate (0.106 g) in water (1ml) was added to a stirred solution ofN-[2-chloro-4-(4-acetamidophenylsulphonyl)phenyl]-2-acetoxy-2-methylpropanamide(Method 16) (0.230 g) in methanol (2 ml) and the mixture was stirred atambient temperature for 2 hours. Water (5 ml) was added and the solutionwas acidified to pH 2-3 with 1M hydrochloric acid. Ethyl acetate (20 ml)was added and the organic layer was washed with water (20 ml) and brine,then dried. Volatile material was removed by evaporation and theoff-white solid was washed with ether to give the title compound (0.150g) as a solid. NMR (CDCl₃):1.3 (s, 6H), 2.2(s, 3H), 7.4 (s, 1H), 7.7 (d,2H), 7.8 (m, 3H), 7.9 (s, 1H), 8.7 (d, 1H), 9.6 (s, 1H); MS (ESP⁻): 409.

EXAMPLES 172-181

[0711] Following the procedure of Example 171 and using the appropriatestarting material the following compounds were prepared. Ex Compound NMRMS SM 172 N-{2-Chloro-4-[4-N-(2,2- (CDCl₃) 1.3 (s, 9H), 1.6 (s, 6H), 451Meth dimethylpropanamido)phenyl- 7.5-7.9 (m, 7H), 8.6 (d, 1H), 9.6 25sulphonyl]phenyl}-2-hydroxy-2- (s, 1H) methylpropanamide 173N-(2-Chloro-4-phenyl- 1.37 (s, 6H), 6.26 (s, 1H), 7.6-7.7 352 Methsulphonylphenyl)-2-hydroxy-2- (m, 3H), 7.9-8.0 (m, 3H), 8.1 (d, 33methylpropanamide 1H), 8.51 (d, 1H), 9.8 (brs, 1H) 174(R)-N-[2-Chloro-4-(4-ureido- 1.6 (s, 3H), 5.9 (s, 2H), 7.1 (d, 432 Methphenylsulphanyl)phenyl]-2- 1H), 7.2 (s, 1H), 7.3 (d, 2H), 7.5 34hydroxy-2-methyl-3,3,3- (d, 2H), 7.7 (s, 1H), 7.8 (d, 1H),trifluoropropanamide 8.7 (s, 1H), 9.6 (s, 1H) 175(R)-N-[2-Chloro-4-(2-ureido- 432 Meth phenylsulphanyl)phenyl]-2- 35hydroxy-2-methyl-3,3,3- trifluoropropanamide 176(R)-N-[2-Fluoro-4-(4-nitro- 1.6 (s, 3H), 7.3 (d, 2H), 7.4 (d, 403 Methphenylsulphanyl)phenyl]-2- 1H), 7.6 (d, 1H), 7.9 (t, 1H), 8.2 39hydroxy-2-methyl-3,3,3- (d, 2H) trifluoropropanamide 177(R)-N-{2-Chloro-4-[4-(2-chloro- 465 Meth acetylamino)phenylsulphanyl] 19phenyl}-2-hydroxy-2-methyl- 3,3,3-trifluoropropanamide 178(R)-N-{2-Chloro-4-[4-(2- 1.6 (s, 3H), 3.2 (s, 6H), 3.8 (s, 516 Methmorpholinoacetylamino)phenyl- 4H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 41sulphanyl]phenyl}-2-hydroxy-2- (d, 2H), 7.7 (d, 2H), 7.8 (s, 1H),methyl-3,3,3- 7.9 (d, 1H), 9.7 (s, 1H) trifluoropropanamide 179(R)-N-{2-Chloro-4-[4-(3-t- 1.2 (s, 9H), 1.6 (s, 3H), 6.1 (s, 488 Methbutylureido)phenylsulphanyl] 1H), 7.1 (d, 1H), 7.2 (s, 1H), 7.3 43phenyl}-2-hydroxy-2-methyl- (d, 2H), 7.4 (d, 2H), 7.7 (s, 1H),3,3,3-trifluoropropanamide 7.8 (d, 1H), 8.6 (s, 1H), 9.6 (s, 1H) 180(R)-N-{2-Chloro-4-[4-(3- 1.6 (s, 3H), 7.0 (t, 1H), 7.1 (d, 508 Methphenylureido)phenylsulphanyl] 1H), 7.3 (m, 3H), 7.4 (t, 4H), 7.6 44phenyl}-2-hydroxy-2-methyl- (d, 2H), 7.8 (s, 1H), 7.9 (d, 1H)3,3,3-trifluoropropanamide 8.8 (s, 1H), 9.0 (s, 1H) 9.6 (s, 1H) 181(R)-N-(2-Chloro-4-{3-t-butoxy-2- (CDCl₃) 1.23 (s, 9H), 1.73 (s, 411 Methhydroxypropylamino}phenyl)-2- 3H), 2.55 (d, 1H), 3.12 (m, 1H), 50hydroxy-2-methyl-3,3,3- 3.27 (m, 1H), 3.4 (m, 1H), 3.5 (m,trifluoropropanamide 1H), 3.95 (s, 2H), 4.24 (s, 1H), 6.53 (dd, 1H),6.67 (s, 1H), 7.95 (d, 1H), 8.34 (s, 1H)

EXAMPLE 182

[0712]N-[2-Chloro-4-(4-mesylaminophenylsulphonyl)phenyl]-2-hydroxy-2-methylpropanamide

[0713] m-Chloroperoxybenzoic acid (50%, 0.55 g) was added to a solutionofN-[2-chloro-4-(4-mesylaminophenylsulphanyl)phenyl]-2-hydroxy-2-methylpropanamide(Example 207) (0.22 g) in DCM (5 ml) and the mixture was stirred atambient temperature for 15 hours. DCM (10 ml) was added, followed bysaturated aqueous sodium carbonate solution (20 ml) and the mixture waspoured onto a Varian Chem Elut column. After 3 minutes the column waswashed through with DCM (20 ml) and the organic fractions concentrated.The residue was purified by flash chromatography eluting with 40-70%ethyl acetate/hexane to give the title compound (0.15 g) as a foam. NMR(CDCl₃): 1.8 (s, 6H), 3.1 (s, 3H), 7.3 (m, 3H), 7.9 (m, 4H), 9.6 (m,2H); MS (ESP⁻): 445; EA: found: C, 45.1; H, 4.4; N, 6.2%, C₁₇H₁₉ClN₂O₆S₂.0.3 H₂O requires C, 45.1; H, 4.4; N, 6.2%.

EXAMPLE 183

[0714] Following the procedure of Example 182 and using the appropriatestarting materials the following compound was prepared. Ex Compound NMRMS SM 183 (R)-N-(1-Oxy-6-methyl-5- 1.6 (s, 3H), 2.5 (s, 3H), 7.7 (m, 403Ex phenylsulphonylpyridin-2-yl)-2- 3H), 7.9 (s, 2H), 8.1 (m, 2H), 211hydroxy-2-methyl-3,3,3- 8.4 (d, 1H) trifluoropropanamide

EXAMPLE 184

[0715]N-[2-Amino-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0716] A suspension ofN-[2-nitro-4-(phenylsulphonyl)phenyl]2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(J. Med. Chem., 1996, 39, 4592) (0.293 g) in methanol (5 ml) was addedto a stirred suspension of 10% palladium on carbon (0.03 g) in methanol(2 ml) under an atmosphere of argon. A solution of ammonium formate(0.176 g) in water (2 ml) was added and the mixture was heated underreflux for 2 hours then cooled. Ethyl acetate (20 ml) was added and themixture was filtered through diatomaceous earth. The filter was washedwith ethyl acetate (2×10 ml) and the filtrates were combined, washedwith water and brine then dried. Volatile material was removed byevaporation to give the title compound (0.261 g) as a solid. NMR: 1.55(s, 3H), 5.3 (s, 2H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.4 (m, 2H), 7.5-7.7(m, 3H), 7.85 (d, 2H), 9.6 (s, 1H); MS (ESP⁻): 387.

EXAMPLE 185

[0717]N-[2-Acetamido-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0718] Acetyl chloride (0.018 ml) was added to an ice-cooled solution ofN-[2-amino-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 184) (0.097 g) in pyridine (1 ml) and the solution was allowedto warm up to ambient temperature over 2 hours. Water was added and themixture was extracted with ethyl acetate. The organic extracts werecombined, washed with brine and dried. Volatile material was removed byevaporation and the residue was purified by chromatography on a silicagel Mega Bond Elut column eluting with 10-40% ethyl acetate/hexane togive the title compound (0.89 g) as a solid. Mp 205-207° C., NMR: 1.5(s, 3H), 2.1 (s, 3H), 7.57-7.75 (m, 4H), 7.8-7.9 (m, 2H) 7.9-8.05 (m,3H), 9.8 (brs, 1H), 10.1 (brs, 1H); MS (ESP⁻): 429.

EXAMPLE 186

[0719] Following the procedure of Example 185 and using methanesulphonylchloride to replace acetyl chloride the following compound was prepared.Ex Compound NMR MS 186 2-Hydroxy-2-methyl-N-[2-mesyl- 1.55 (s, 3H), 3.0(s, 3H), 7.5-7.75 465 amino-4-(phenylsulphonyl)phenyl]- (m, 3H), 7.8-8.0(m, 5H), 8.3 (d, 3,3,3-trifluoropropanamide 1H), 9.6 (brs, 1H), 10.1(brs, 1H)

EXAMPLE 187

[0720](R)-N-[2-Chloro-4-(2-fluorophenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0721] Tetrakis(triphenylphosphine)palladium(0) (0.147 g) was added to adeoxygenated mixture of(R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (1.0 g), 2-fluorothiophenol (0.263 ml) and sodiummethoxide (0.288 g) in ethanol (50 ml). The mixture was then furtherdeoxygenated by evacuation and refilling with argon (3 cycles), and thenheated under reflux with stirring under argon for 18 hours. The mixturewas treated with a further portion oftetrakis(triphenylphosphine)palladium(0) (0.147 g), heated for a further24 hours then cooled and filtered. Volatile material was removed byevaporation and the residue was purified by flash chromatography elutingwith 20% ethyl acetate/hexane to give the title compound (0.906 g) as anoil. NMR (CDCl₃): 1.75 (s, 3H), 3.58 (s, 1H), 7.1 (t, 2H), 7.2-7.35 (m,3H), 7.37 (d, 1H), 8.3 (d, 1H), 8.82 (brs, 1H); MS (ESP⁻): 392.

EXAMPLES 188-196

[0722] Following the procedure of Example 187 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR and MS 188 (R)-N-[2-Chloro-4-(4-fluorophenylsulphanyl) (CDCl₃): 1.74(s, 3H), 3.79 (s, 1H), phenyl]-2-hydroxy-2-methyl-3,3,3- 7.04 (t, 2H),7.2 (dd, 1H), 7.27 (d, trifluoropropanamide 1H), 7.38 (dd, 2H), 8.27 (d,1H), 8.87 (brs, 1H); MS (ESP⁺): 394 (M + H)⁺. 189(R)-N-[2-Chloro-4-{4-(methylsulphanyl) 1.57 (s, 3H), 3.29 (s, 3H),7.2-7.4 (m, phenylsulphanyl}phenyl]-2-hydroxy-2-methyl- 6H), 7.8 (brs,1H), 7.9 (d, 1H), 9.7 3,3,3-trifluoropropanamide (brs, 1H)  190¹(R)-N-[2-Chloro-4-{4-(ethoxycarbonyl) (CDCl₃): 1.4 (t, 3H), 1.79 (s,3H), phenylsulphanyl}phenyl]-2-hydroxy-2-methyl- 3.68 (s, 1H), 4.35 (q,2H), 7.24 (d, 3,3,3-trifluoropropanamide 2H), 7.41 (dd, 1H), 7.51 (d,1H), 7.92 (d, 2H), 8.42 (d, 1H), 9.0 (brs, 1H)  191²(R)-N-[2-Chloro-4-methylsulphanylphenyl]-2- (CDCl₃): 1.76 (s, 3H), 2.5(s, 3H), hydroxy-2-methyl-3,3,3-trifluoropropanamide 3.82 (brs, 1H),7.19 (dd, 1H). 7.3 (d, 1H), 8.28 (d, 1H), 8.8 (brs, 1H) 192(R)-N-[2-Chloro-4-(pyrid-4-ylsulphanyl) (CDCl₃): 1.68 (s, 3H), 6.98 (m,2H), phenyl]-2-hydroxy-2-methyl-3,3,3- 7.26 (s, 1H), 7.5 (dd, 1H), 7.6(d, trifluoropropanamide 1H), 8.32 (m, 2H), 8.56 (d, 1H), 9.38 (brs, 1H)193 (R)-N-[2-Fluoro-4-(4-fluorophenylsulphanyl) (CDCl₃): 1.73 (s, 3H),3.63 (s, 1H), phenyl]-2-hydroxy-2-methyl-3,3,3- 7.02-7.07 (m, 4H),7.36-7.42 (m, trifluoropropanamide 2H), 8.19-8.23 (m, 1H), 8.50 (s, 1H);MS (ESP⁻): 376. 194 (R)-N-[2-Fluoro-4-(4-methylsulphanylphenyl- 1.6 (s,3H), 7.05 (d, 1H), 7.1 (d, 1H),sulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3- 7.3 (d, 2H), 7.35 (d, 2H),7.5-7.7 (m, trifluoropropanamide 2H), 9.6 (s, 1H); MS (ESP⁻): 404. 195(R)-N-[2-Fluoro-4-(2-fluorophenylsulphanyl) 1.6 (s, 3H), 7.1 (d, 1H),7.15-7.5 phenyl]-2-hydroxy-2-methyl-3,3,3- (brm, 5H), 7.6 (brs, 1H), 7.7(t, 1H), trifluoropropanamide 9.6 (brs, 1H); MS (ESP⁻): 376.  196²(R)-N-[2-Fluoro-4-(methylsulphanyl)phenyl]- (CDCl₃) 1.73 (s, 3H), 2.47(s, 3H), 2-hydroxy-2-methyl-3,3,3- 3.63 (s, 1H), 7.0-7.05 (m, 2H), 8.17trifluoropropanamide (t, 1H), 8.83 (s, 1H)

EXAMPLE 197

[0723](R)-N-(2-Chloro-4-iodonhenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0724] Oxalyl chloride (1.07 ml) was added dropwise to a stirredsuspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid(Method 9) (1.95 g) in DCM (42 ml) and DMF (0.8 ml). The mixture wasstirred at ambient temperature for 2 hours and was then added over 35minutes to a solution of 2-chloro-4-iodoaniline (2.5 g) and2,6-di-t-butylpyridine (2.94 ml) in DCM (40 ml) and stirred a further 18hours. Volatile material was removed by evaporation and the residue waspurified by flash chromatography on silica gel eluting with DCM to givethe title compound (2.85 g) as a solid. NMR: 1.6 (s, 3H), 7.7 (m, 2H),7.8 (d, 1H), 7.9 (brs, 1H); MS (ESP⁻): 392.

EXAMPLES 198-201

[0725] Following the procedure of Example 197 and using the appropriatestarting material the following compounds were prepared. Ex Compound NMRMS SM 198 (R)-N-(2-Chloro-4-benzyl- 1.7 (s, 3H), 3.75 (brs, 1H), 358Meth 30 phenyl)-2-hydroxy-2-methyl- 3.95 (s, 2H), 7.1-7.25 (m,3,3,3-trifluoropropanamide 7H), 8.15 (d, 1H), 8.75 (brs, 1H) 199(R)-N-[2-Fluoro-4-iodophenyl]- (CDCl₃) 1.56 (s, 3H), 3.57 3762-Fluoro-4- 2-hydroxy-2-methyl-3,3,3- (s, 1H), 7.44-7.50 (m, 2H),iodoaniline trifluoropropanamide 8.08 (t, 2H), 8.56 (brs, 1H)  200¹N-[2-Fluoro-4-(4-methyl- (CDCl₃) 2.47 (s, 3H), 3.94 422 Meth 6 sulphanylphenylsulphanyl) (brs, 2H), 6.15 (t, 1H), phenyl]-2-hydroxy-2-6.94-7.00 (d, 1H), 7.02- difluoromethyl-3,3- 7.05 (d, 1H), 7.18-7.21 (d,difluoropropanamide 2H), 7.28-7.31 (d, 2H), 8.15 (t, 1H), 8.52 (s, 1H) 201² (R)-N-[2-Bromo-4-{4-methyl- (CDCl₃) 1.76 (s, 3H), 2.5 466 Meth 11sulphanylphenylsulphanyl} (s, 3H), 3.66 (s, 1H), 7.2 (d,phenyl]-2-hydroxy-2-methyl- 2H), 7.3-7.33 (m, 3H), 7.473,3,3-trifluoromethyl- (d, 1H), 8.25 (d, 1H), 9.8 propanamide (s, 1H)

EXAMPLE 202

[0726](R)-N-{2-Chloro-4-([5-ethoxycarbonyl-3-pyridyl]sulphanyl)phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0727] Caesium fluoride (0.26 g) was added to a solution of(R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(0.74 g) (Method 28) in anhydrous DMA (5 ml) under argon and the mixturewas stirred for 17 hours. Copper(I) chloride (0.17 g) followed by3-bromo-5-carboethoxypyridine (0.37 g) were added and the mixture washeated to 155° C. for 4 hours and allowed to cool to ambienttemperature. Ethyl acetate (20 ml) and brine (20 ml) were added and themixture was filtered through a pad of diatomaceous earth which waswashed with ethyl acetate (3×50 ml). The filtrates were combined, washedwith brine (3×50 ml) and then dried. Volatile material was removed byevaporation and the residue was purified on a silica gel Mega Bond Elutcolumn eluting with 10-40% ethyl acetate/iso-hexane to give the titlecompound (in 53% yield) as a foam. NMR (CDCl₃): 1.39 (t, 3H), 1,57 (s,3H), 4.00 (s, 1H), 4.40 (q, 2H), 7.34-7.37 (m, 1H), 7.46 (d, 1H), 8.18(s, 1H), 8.42 (d, 1H), 8.62 (s, 1H), 9.03 (s, 1H), 9.04 (s, 1H); MS(ESP⁻): 447.

EXAMPLE 203

[0728] By the method of Example 202 and using the appropriate startingmaterials the following compound was prepared. Ex Compound NMR MS SM 203(R)-N-{2-Chloro-4-(4-{pyrimidin- 1.6 (s, 3H), 7.38-7.52 (m, 4H), 452 Ex197 2-yl}phenylsulphanyl)phenyl}-2- 7.65 (d, 1H), 7.9 (brs, 1H), 8.06and hydroxy-2-methyl-3,3,3- (d, 1H), 8.38 (d, 2H), 8.9 (d, Methtrifluoropropanamide 2H), 9.79 (brs, 1H) 52

EXAMPLE 204

[0729] Following the procedure of Method 22 (see below) and usingExample 197 as the starting material the following compound wasprepared. Ex Compound NMR 204 (R)-N-[2-Chloro-4-{4-nitrophenyl- (CDCl₃)1.8 (s, 3H), 5.0 (s, 1H), 7.2 (d, sulphanyl}phenyl]-2-hydroxy-2-methyl-2H), 7.5 (d, 1H), 7.6 (s, 1H), 8.1 (d, 3,3,3-trifluoropropanamide 2H),8.6 (d, 1H), 9.3 (s, 1H).

EXAMPLE 205

[0730]N-(2-Fluoro-4-phenylsulphanylphenyl)-2-hydroxy-2-methylpropanamide

[0731] 2-Acetoxy-2-methylpropanoyl chloride (0.47 ml) was added to asolution of 2-fluoro-4-phenylsulphanylaniline (Method 7) (0.64 g) andpyridine (0.28 ml) in DCM (10 ml). The solution was stirred at ambienttemperature for 90 minutes then volatile material was removed byevaporation. The residue was dissolved in methanol (20 ml) and asolution of lithium 2515 hydroxide monohydrate (0.378 g) in water (2.5ml) was added. Stirring was continued for another 1 hour then themixture was acidified to pH 1 with 2M hydrochloric acid and concentratedby evaporation to about 5 ml. Water (10 ml) was added and the productwas extracted with ethyl acetate. Organic layers were washed with brinethen combined and dried. Volatile material was removed by evaporationand the residue was purified by chromatography on a silica gel Mega BondElut column eluting with 10-20% ethyl acetate/hexane to yield the titlecompound (0.784 g) as a solid. Mp 91-92.5° C.; NMR: 1.34 (s, 6H), 5.96(s, 1H), 7.15 (d, 1H), 7.23 (dd, 1H), 7.27-7.4 (m, 5H), 8.02 (t, 1H),9.3 (s,1H); MS (ESP⁻): 304; EA: found: C, 62.8; H, 5.3; N. 4.5; S.10.5%; C₁₆H₁₆FNO₂S requires: C, 62.9; H, 5.3; N, 4.6; S, 10.5%.

EXAMPLE 206

[0732] Following the procedure of Example 205 using the appropriatestarting materials the following compound was prepared. Ex Compound HPLCMS SM 206 (R)-N-[2-Chloro-4-(2-nitro- 8.08 minutes 402 Methanilino)phenyl]-2-hydroxy-2- (HPLC Method d) 47methyl-3,3,3-trifluoropropanamide

EXAMPLE 207

[0733]N-[2-Chloro-4-(4-mesylaminophenylsulphanyl)phenyl]-2-hydroxy-2-methylpropanamide

[0734] A solution of lithium hydroxide monohydrate (0.177 g) in water(1.8 ml) was added to a stirred solution ofN-{2-chloro-4-[4-(N,N-dimesylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methylpropanamide(Method 26) (0.45 g) in methanol (3.5 ml) and the mixture was stirred atambient temperature for 4 hours. Water (3 ml) was added and the solutionwas acidified to pH 2-3 with 1M hydrochloric acid. DCM (20 ml) was addedand the organic layer was washed with water (20 ml) and brine, thendried. Volatile material was removed by evaporation and the residue waspurified by flash chromatography eluting with 30-70% ethylacetate/hexane to give the title compound (0.30 g) as a solid. Mp138-140° C.; NMR (CDCl₃): 1.5 (s, 6H), 3.0 (s, 3H), 7.1-7.4 (m, 7H), 8.4(d, 1H), 9.3 (s, 1H); MS (ESP⁻):413; EA: found: C, 48.9; H, 4.4; N,6.5%; C₁₇H₁₉ClN₂O₄S₂ requires C, 49.2; H, 4.6; N, 6.8%.

EXAMPLES 208-209

[0735] Following the procedure of Method 30 (see below) and using theappropriate starting materials the following compounds were prepared. ExCompound NMR MS SM 208 (R)-N-(2-Chloro-4-amino- 1.53 (s, 3H), 5.32 (s,2H), 6.50 281 Meth phenyl)-2-hydroxy-2-methyl- (d, 1H), 6.66 (s, 1H),7.39 (d, 60 3,3,3-trifluoropropanamide 1H), 7.45 (s, 1H), 9.30 (s, 1H)209 (R)-N-(2-Methyl-4-amino- (CDCl₃) 1.69 (s, 3H), 2.15 (s, 261 Methphenyl)-2-hydroxy-2- 3H), 3.60 (brs, 2H), 4.02 (brs, 62methyl-3,3,3-trifluoropropanamide 1H), 6.48-6.57 (m, 2H), 7.28- 7.35 (m,1H), 7.62 (brs, 1H).

EXAMPLE 210

[0736](R)-N-(2-Chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0737] Trifluoroacetic anhydride (5 ml) was added to(R)-N-(2-chloro-4-methylsulphinyl-phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 92) (0.188 g). The mixture was stirred and heated under refluxfor 45 minutes then cooled and evaporated to dryness. A mixture oftriethylamine (5 ml) and methanol (5 ml) was added to the residue. Thismixture was stirred for a further 45 minutes then evaporated to dryness.The residue was dissolved in chloroform (50 ml), washed with saturatedaqueous ammonium chloride solution (50 ml), dried and concentrated byevaporation to give the title compound (0.177 g) as a gum which was usedwithout purification. MS (ESP⁻): 298.

EXAMPLE 211

[0738] The indicated starting material was coupled with an appropriatethiol or halide using the method of Example 250 and acylated using theprocedure of Example 197. Ex Compound MS SM 211 (R)-N-[6-Methyl-5- 3572-methyl-3-bromo- phenylsulphanylpyridin-2-yl]-2- (M + H)⁺6-aminopyridine hydroxy-2-methyl-3,3,3- trifluoropropanamide

EXAMPLE 212

[0739] Following the procedure of Method 63 (see below) and using theappropriate starting material the following compound was prepared. ExCompound NMR SM 212¹ (R)-N-[2-Chloro-4-(4-mesyl (CDCl₃) 1.73 (s, 3H),3.08 (s, Ex 189 phenylsulphonyl)phenyl]-2-hydroxy- 3H), 3.7 (brs, 1H),7.89 (dd, 1H), 2-methyl-3,3,3-trifluoropropanamide 8.02 (d, 1H),8.08-8.15 (m, 4H), 8.67 (d, 1H), 9.33 (brs, 1H)

EXAMPLES 213-214

[0740] Following the procedure of Method 13 (see below) and using theappropriate starting material the following compounds were prepared. ExCompound NMR MS SM 213 (R)-N-{2-Chloro-4-[2-(methoxy- 1.6 (s, 3H), 3.85(s, 3H), 7.6 (m, 464 Ex carbonyl)phenylsulphonyl]- 1H), 7.8-7.9 (m, 2H),7.95 (dd, 1H), 105 phenyl}-2-hydroxy-2-methyl- 7.9-8.05 (brs, 1H), 8.1(d, 1H), 8.2- 3,3,3-trifluoropropanamide 8.35 (m, 2H), 9.9 (brs, 1H) 214(R)-N-{2-Chloro-4-[2-(ethoxy- 1.3 (t, 3H), 1.58 (s, 3H), 4.3 (q, 478 Excarbonyl)phenylsulphonyl]- 2H), 7.65 (dd, 1H), 7.8 (m, 2H), 106phenyl}-2-hydroxy-2-methyl- 7.95 (dd, 1H), 9.0 (brs, 1H), 8.1 (d,3,3,3-trifluoropropanamide 1H), 8.2 (dd, 1H), 8.3 (d, 1H), 9.95 (brs,1H)

EXAMPLE 215

[0741](R)-N-{2-Chloro-4-[4-(N,N-dimethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0742] Oxalyl chloride (0.45 ml) was added to a stirred suspension of(R)-N-[2-chloro-4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 121) (1.81 g) in DCM (100 ml) containing DMF (10 drops). Themixture was stirred for 5 hours and then a solution of dimethylamine(4.2 ml, 2M solution in methanol) was added, and the solution wasstirred overnight. The reaction mixture was washed with dilutehydrochloric acid solution (2×25 ml) then dried. Volatile material wasremoved by evaporation and the residue was purified by chromatography ona silica gel Mega Bond Elut column eluting with 0-10% methanol/DCM toyield the title compound (0.68 g) as a solid. M.p. 120.5° C. (MettlerFP62 apparatus); NMR: (CDCl₃): 1.70 (s, 3H), 2.90 (s, 3H), 3.10 (s, 3H),5.20 (s, 1H), 7.55 (d, 2H), 7.85 (d, 1H), 7.90-8.00 (m, 3H), 8.60 (d,1H), 9.40 (s, 1H); MS (ESP⁻): 477.

EXAMPLES 216-249

[0743] Following the procedure of Example 215 using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM 216 (R)-N-{2-Chloro-4-[4-(N,N- (CDCl₃) 1.05-1.15 (brm, 3H),1.2- 505 Ex diethylcarbamoyl)phenyl- 1.3 (brm, 3H), 1.7 (s, 3H), 3.1-3.3121 sulphonyl]phenyl}-2-hydroxy- (m, 2H), 3.5-3.65 (m, 2H), 5.1 (s,2-methyl-3,3,3- 1H), 7.5 (d, 2H), 7.85 (d, 1H), 7.95-trifluoropropanamide 8.0 (m, 3H), 8.6 (d, 1H), 9.4 (brs, 1H) 217(R)-N-(2-Chloro-4-{4-[N-(3- 1.65 (s, 3H), 1.7-1.75 (m, 2H), 507 Exhydroxypropyl)carbamoyl] 3.25-3.35 (m, 2H), 3.4-3.5 (m, 2H), 121phenylsulphonyl}phenyl)-2- 4.45 (dd, 1H), 7.95-8.05 (m, 4H),hydroxy-2-methyl-3,3,3- 8.1 (d, 2H), 8.2 (s, 1H), 8.35 (d,trifluoropropanamide 1H), 8.6-8.7 (m, 1H), 9.9 (brs, 1H) 218(R)-N-(2-Chloro-4-{4-[N-(2,3- 1.6 (s, 3H), 3.1-3.2 (m, 1H), 3.3-3.5 523Ex dihydroxypropyl)carbamoyl] (m, 2H), 3.6-3.7 (m, 2H), 7.85 (brs, 121phenylsulphonyl}phenyl)-2- 1H), 7.95-8.0 (m, 1H), 8.05-8.10hydroxy-2-methyl-3,3,3- (m, 3H), 8.10-8.15 (m, 1H), 8.2 (d,trifluoropropanamide 1H), 8.3 (d, 1H), 8.7 (dd, 1H), 9.9 (s, 1H) 219R)-N-[2-Chloro-4-(4- (CDCl₃) 1.65 (s, 3H), 7.60 (s, 1H), 449 Excarbamoylphenylsulphonyl) 7.95 (dd, 1H), 8.0-8.05 (m, 4H), 121phenyl]-2-hydroxy-2-methyl- 8.05-8.1 (m, 1H), 8.1-8.2 (m, 2H),3,3,3-trifluoropropanamide 8.3 (d, 1H), 9.9 (s, 1H) 220(R)-N-{2-Chloro-4-[4-(4-t- (CDCl₃) 1.45 (s, 9H), 1.7 (s, 3H), 618 Exbutoxycarbonylpiperazin-1-yl- 3.25-3.55 (brm, 7H), 3.7-3.8 (m, 121carbonyl)phenylsulphonyl] 2H), 7.5 (d, 2H), 7.85 (dd, 1H),phenyl}-2-hydroxy-2-methyl- 7.95-8.0 (m, 3H), 8.6 (d, 1H), 9.353,3,3-trifluoropropanamide (s, 1H) 221 (R)-N-(2-Chloro-4-{4-[N-(2- 1.25(s, 6H), 1.6 (s, 3H), 3.5 (d, 521 Ex hydroxy-1.1-dimethylethyl) 2H), 4.8(dd, 1H), 7.75 (s, 1H), 7.9 121 carbamoyl]phenylsulphonyl} (d, 2H), 7.95(dd, 2H), 8.05 (d, 2H), phenyl)-2-hydroxy-2-methyl- 8.15 (d, 2H), 8.3(d, 1H), 9.90 (s, 3,3,3-trifluoropropanamide 1H) 222(R)-N-{2-Chloro-4-[4-(N- (CDCl₃) 1.75 (s, 3H), 5.2 (brs, 1H), 527 Expyrimidin-2-ylcarbamoyl) 6.6 (dd, 1H), 7.1 (dd, 1H), 7.8-7.9 121phenylsulphonyl]phenyl}-2- (m, 1H), 8.0 (d, 1H), 8.05 (s, 1H),hydroxy-2-methyl-3,3,3- 8.25 (d, 2H), 8.60-8.7 (m, 3H), 9.05trifluoropropanamide (s, 1H), 9.6 (s, 1H) 223 (R)-N-{2-Chloro-4-[4-(N-(CDCl₃) 1.7 (s, 3H), 3.0 (d, 3H), 4.2 463 Ex methylcarbamoyl)phenyl- (s,1H), 6.2 (brs, 1H), 7.8-7.9 (m, 121 sulphonyl]phenyl}-2-hydroxy- 3H),7.9-8.0 (m, 3H), 8.6 (d, 1H), 2-methyl-3,3,3- 9.35 (brs, 1H)trifluoropropanamide 224 (R)-N-{2-Chloro-4-[2-(4- (DMSO-δ₆ + AcOH-δ₄)1.55 (s, 532 Ex methylpiperazin-1-ylcarbonyl) 3H), 2.68 (brs, 3H),2.97-3.02 (brm, 125 phenylsulphonyl]phenyl}-2- 2H), 3.10-3.13 (brm, 2H),3.30-3.32 hydroxy-2-methyl-3,3,3- (brm, 2H), 3.84-3.86 (brm, 2H),trifluoropropanamide 7.40 (d, 1H), 7.6 (t, 1H), 7.7 (t, 1H), 7.89-7.94(m, 1H), 8.05-8.07 (m, 2H), 8.32 (d, 1H) 225 (R)-N-{2-Chloro-4-[2-(DMSO-δ₆ + AcOH-δ₄) 1.55 (s, 519 Ex (morpholinocarbonyl)phenyl- 3H),3.02-3.07 (m, 2H), 3.52-3.94 125 sulphonyl]phenyl}-2-hydroxy- (m, 6H),7.35 (d, 1H), 7.58 (t, 1H), 2-methyl-3,3,3- 7.89-7.92 (m, 1H), 8.03 (d,1H), trifluoropropanamide 8.10 (s, 1H), 8.32 (d, 1H); 226(R)-N-{2-Chloro-4-[2- (At 373K): 1.64 (s, 3H), 3.0-3.06 521 Ex(thiazolidin-3-ylcarbonyl) (brm, 2H), 3.40-3.45 (brm, 1H), 125phenylsulphonyl]phenyl}-2- 3.87-3.9 (brm, 1H), 4.12-4.2 (brm,hydroxy-2-methyl-3,3,3- 1H), 4.61-4.67 (brm, 1H), 7.47 (d,trifluoropropanamide 1H), 7.68 (t, 1H), 7.78 (t, 1H), 7.95 (d, 1H),8.09-8.12 (m, 1H), 8.31 (d, 1H), 9.71 (brs, 1H) 227(R)-N-[2-Chloro-4-(N,N- 0.92-0.97 (t, 3H), 1.06-1.1 (t, 3H), 445 Exdiethylcarbamoylmethyl- 1.62 (s, 3H), 3.15-3.2 (q, 2H), 3.33- 314sulphonyl)phenyl]-2-hydroxy- 3.38 (q, 2H), 4.68 (s, 2H), 7.86-7.92-methyl-3,3,3- (m, 1H), 8.02 (s, 1H), 8.29 (d, 1H),trifluoropropanamide 9.94 (s, 1H) 228 (R)-N-[2-Chloro-4-(carbamoyl- 1.62(s, 3H), 4.29 (s, 2H), 7.86 (d, 387 Ex methylsulphonyl)phenyl]-2- 1H),8.0 (s, 1H), 8.3 (d, 1H), 9.92 314 hydroxy-2-methyl-3,3,3- (s, 1H)trifluoropropanamide 229 (R)-N-{2-Chloro-4-[N-(2- 1.63 (s, 3H),3.02-3.07 (m, 2H), 431 Ex hydroxyethyl)carbamoylmethyl 3.28-3.34 (m,2H), 4.44 (s, 2H), 314 sulphonyl]phenyl}-2-hydroxy- 4.65 (t, 1H),7.84-7.86 (m, 2H), 8.0 2-methyl-3,3,3- (s, 1H), 8.31 (d, 1H).trifluoropropanamide 230 (R)-N-[2-Chloro-4-(N-iso- 0.97 (d, 6H), 1.63(s, 3H), 3.65- 429 Ex propylcarbamoylmethyl- 3.73 (m, 1H), 4.26 (s, 2H),7.81- 314 sulphonyl)phenyl]-2-hydroxy- 7.84 (m, 1H), 7.92 (s, 1H), 8.31(d, 2-methyl-3,3,3- 1H). trifluoropropanamide 231 (R)-N-[2-Chloro-4-(N-1.62 (s, 3H), 4.81 (s, 2H), 6.51-6.55 467 Ex pyrimidin-2-ylcarbamoyl-(m, 2H), 7.2-7.23 (m, 1H), 7.88- (M + H)⁺ 314 methylsulphonyl)phenyl]-2-7.91 (m, 1H), 7.97 (s, 1H), 8.33 (d, hydroxy-2-methyl-3,3,3- 1H), 9.95(s, 1H), 10.9 (s, 1H) trifluoropropanamide 232(R)-N-{2-Chloro-4-[2-(N,N- 1.0 (t, 3H), 1.14 (t, 3H), 1.60 (s, 473 Exdiethylcarbamoyl)phenyl- 3H), 3.05 (q, 2H), 3.44 (m, 2H), 292sulphanyl]phenyl}-2-hydroxy- 7.30 (m, 3H), 7.41 (m, 2H), 7.49 (s,2-methyl-3,3,3- 1H), 7.86 (brs, 1H), 7.95 (d, 1H), trifluoropropanamide9.73 (brs, 1H) 233 (R)-N-[2-Chloro-4-(4- 1.60 (s, 3H), 7.3 (d, 2H), 7.4(d, 435 Ex carbamoylphenylsulphinyl) 2H), 7.50 (dd, 1H), 7.65 (d, 1H),(M + H)⁺ 280 phenyl]-2-hydroxy-2-methyl- 7.8-8.0 (m, 3H), 8.1 (d, 1H),9.80 3,3,3-trifluoropropanamide (s, 1H) 234 (R)-N-[2-Chloro-4-(4-N,N-(CDCl₃) 1.05-1.25 (m, 6H), 1.7 (s, 475 Ex diethylcarbamoylphenyl- 3H),3.2-3.3 (m, 2H), 3.4-3.5 (m, (M + H)⁺ 291 sulphanyl)phenyl]-2-hydroxy-2H), 5.25 (s, 1H), 7.2-7.3 (m, 3H), 2-methyl-3,3,3- 7.35 (d, 1H),7.45-7.5 (m, 1H), 7.95 trifluoropropanamide (dd, 1H), 8.4 (d, 1H), 9.2(s, 1H) 235 (R)-N-[2-Chloro-4-(4-N,N- 1.60 (s, 3H), 2.95 (d, 6H), 7.3(d, 464 Ex dimethylcarbamoylphenyl- 2H), 7.35-7.4 (m, 3H), 7.6 (s, 1H),(M + H)⁺ 280 sulphinyl)phenyl]-2-hydroxy- 7.8-8.0 (m, 1H), 8.05 (d, 1H),9.8 2-methyl-3,3,3- (s, 1H) trifluoropropanamide 236(R)-N-[2-Chloro-4-(4-(2- 1.6 (s, 3H), 1.75 (s, 1H), 3.9-4.0 480 Exhydroxyethoxycarbonyl)phenyl (m, 2H), 4.4-4.5 (m, 2H), 7.35 (d, (M + H)⁺280 sulphinyl)phenyl]-2-hydroxy- 2H), 7.5 (d, 1H), 7.7 (s, 1H), 7.8-2-methyl-3,3,3- 8.0 (m, 3H), 8.1 (d, 1H), 9.8 (s, 1H)trifluoropropanamide 237 (R)-N-[2-Chloro-4-(4-{2- (CDCl₃) 1.75 (s, 3H),2.4-2.6 (m, 532 Ex morpholinoethylamino 4H), 2.6-2.7 (m, 2H), 3.5-3.6(m, (M + H)⁺ 291 carbonyl}phenylsulphanyl) 2H), 3.7-3.8 (m, 4H), 6.8-6.9(s, phenyl]-2-hydroxy-2-methyl- 1H), 7.2-7.3 (m, 3H), 7.35 (dd, 1H),3,3,3-trifluoropropanamide 7.5 (s, 1H), 7.65 (d, 2H), 8.4 (d, 1H), 9.25(s, 1H) 238 (R)-N-[2-Chloro-4-(4-{3- 1.0-1.05 (m, 1H), 1.05-1.10 (m, 503Ex hydroxypiperidin-1-yl- 4H), 1.3-1.4 (s, 2H), 1.6 (s, 3H), (M + H)⁺291 carbonyl}phenylsulphanyl) 4.0-4.1 (m, 3H), 7.25-7.4 (m, 4H),phenyl]-2-hydroxy-2-methyl- 7.4-7.45 (m, 1H), 7.6 (s, 1H), 7.853,3,3-trifluoropropanamide (s, 1H), 8.05 (d, 1H), 9.80 (s, 1H) 239(R)-N-[2-Chloro-4-(4-{N-[5- (CDCl₃) 1.75 (s, 3H), 2.2 (s, 3H), 497 Exmethylpyrazol-3-yl] 5.35 (s, 1H), 5.6 (brs, 2H), 7.2-7.25 (M + H)⁺ 291carbamoyl}phenylsulphanyl) (m, 3H), 7.45 (dd, 1H), 7.55 (d,phenyl]-2-hydroxy-2-methyl- 1H), 8.0 (d, 2H), 8.4 (d, 1H), 9.0 (s,3,3,3-trifluoropropanamide 1H) 240 (R)-N-[2-Chloro-4-(4-{N- 1.6 (s, 3H),5.5 (s, 2H), 5.85 (d, 484 Ex [isoxazol-3-yl]carbamoyl} 1H), 7.35 (d,2H), 7.5 (d, 1H), 7.95 291 phenylsulphanyl)phenyl]-2- (d, 1H), 8.1 (d,1H), 8.3 (d, 2H), 8.8 hydroxy-2-methyl-3,3,3- (s, 1H), 9.8 (s, 1H)trifluoropropanamide 241 (R)-N-{2-Chloro-4-[3-(4- 1.6 (s, 3H), 2.23 (m,5H), 2.36 (brs, 532 Ex methylpiperazin-1-ylcarbonyl) 1H), 3.2 (brs, 2H),3.6 (brs, 2H), 170 phenylsulphonyl]phenyl}-2- 7.7 (d, 2H), 7.9-8.13 (m,4H), 8.23 hydroxy-2-methyl-3,3,3- (s, 1H), 8.31 (d, 1H), 9.9 (brs, 1H)trifluoropropanamide 242 (R)-N-{2-Chloro-4-[3-(N- 1.58 (s, 3H), 2.8 (d,3H), 7.71 (t, 463 Ex methylcarbamoyl)phenyl- 1H), 8.0 (d, 1H), 8.12 (m,3H), 8.3 170 sulphonyl]phenyl}-2-hydroxy- (d, 1H), 8.38 (s, 1H), 8.7 (d,1H) 2-methyl-3,3,3- trifluoropropanamide 243 (R)-N-{2-Chloro-4-[3- 1.59(s, 3H), 1.84 (m, 4H), 3.32 (m, 505 Ex (pyrrolidin-1-ylcarbonyl) 2H),3.48 (t, 2H), 7.68 (t, 1H), 7.83 (M + H)⁺ 170 phenylsulphonyl]phenyl}-2-(d, 1H), 7.98-8.1 (m, 3H), 8.19 (s, hydroxy-2-methyl-3,3,3- 1H), 8.3 (d,1H) trifluoropropanamide 244 (R)-N-{2-Chloro-4-[3- 1.58 (s, 3H), 7.6 (s,1H), 7.7 (t, 1H), 449 Ex carbamoylphenylsulphonyl] 8.0 (d, 1H), 8.13 (m,3H), 8.25 (brs, 170 phenyl}-2-hydroxy-2-methyl- 1H), 8.3 (d, 1H), 8.41(s, 1H) 3,3,3-trifluoropropanamide 245 (R)-N-{2-Chloro-4-{3-[N′-(2- 1.58(s, 3H), 2.20 (s, 6H), 2.44 (m, 522 Ex N,N-dimethylaminoethyl) 2H), 3.37(m, 2H), 7.71 (t, 1H), 170 carbamoyl]phenylsulphonyl} 7.99 (dd, 1H),8.14 (m, 3H), 8.32 phenyl}-2-hydroxy-2-methyl- (d, 1H), 8.4 (s, 1H), 8.7(t, 1H) 3,3,3-trifluoropropanamide 246 (R)-N-{2-Chloro-4-[3-N,N- (CDCl₃)1.71 (s, 3H), 2.98 (s, 3H), 477 Ex dimethylcarbamoylphenyl- 3.12 (s,3H), 4.35 (s, 1H), 7.6 (m, 170 sulphonyl]phenyl}-2-hydroxy- 2H), 7.84(dd, 1H), 7.98 (m, 3H), 2-methyl-3,3,3- 8.6 (d, 1H), 9.23 (s, 1H)trifluoropropanamide 247 (R)-N-{2-Chloro-4-[3- Retention time 25.39minutes 533 Ex (pyrrolidin-1-ylcarbonyl) (HPLC Method c) 170phenylsulphonyl]phenyl}-2- hydroxy-2-methyl-3,3,3- trifluoropropanamide248 (R)-N-{2-Chloro-4-[3- Retention time 27.28 minutes 519 Ex(morpholinocarbonyl)phenyl- (HPLC Method c) 170sulphonyl]phenyl}-2-hydroxy- 2-methyl-3,3,3- trifluoropropanamide 249(R)-N-{2-Chloro-4-[3- Retention time 29.70 minutes 535 Ex(thiomorpholinocarbonyl) (HPLC Method c) 170 phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3- trifluoropropanamide

EXAMPLE 250

[0744](R)-N-{2-Chloro-4-[4-(pyrrolidin-1-ylsulphonyl)phenylsulphanyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0745] Copper (1) chloride (0.038 g) was added to a mixture of(R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 210) (0.21 g), N-(4-iodobenzenesulphonyl)pyrrolidine (0.258 g)and sodium methoxide (0.042 g) in DMA (5 ml). The mixture was heated at150° C. with stirring for 4 hours then cooled and the DMA removed byevaporation. Ethyl acetate (20 ml) and water (20 ml) was added and themixture was filtered. The aqueous layer was extracted with ethyl acetate(3×20 ml) and the organic layers were combined and dried. Volatilematerial was removed by evaporation and the residue was purified on asilica gel Mega Bond Elut column, eluting with methanol/DCM 0-10% togive the title compound (0.16 g) as a solid. NMR (CDCl₃): 1.75 (s, 3H),1.75-1.85 (m, 4H), 3.2-3.3 (m, 4H), 4.0 (s, 1H), 7.2-7.3 (m,2H),7.4-7.45 (m, 1H),7.7 (d, 2H), 8.45 (d, 1H), 9.15 (s, 1H); MS (ESP⁻):507.

EXAMPLES 251-279

[0746] Following the procedure of Example 250 using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM 251 (R)-N-{2-Chloro-4-[4-(dimethyl- (CDCl₃) 1.75 (s, 3H), 2.7481 Ex aminosulphonyl)phenylsulphanyl] (s, 6H), 3.6 (s, 1H), 7.25 210phenyl}-2-hydroxy-2-methyl- (d, 2H), 7.45 (dd, 1H), 7.63,3,3-trifluoropropanamide (d, 1H), 7.7 (d, 2H), 8.45 (d, 1H), 9.1 (s,1H) 252 (R)-N-[2-Chloro-4-(4-hydroxy- (CDCl₃) 1.75 (s, 3H), 4.1 390 Exphenylsulphanyl)phenyl]-2-hydroxy- (s, 1H), 6.75 (d, 2H), 6.85 1972-methyl-3,3,3- (d, 2H), 7.3-7.4 (m, 3H), trifluoropropanamide 8.2 (d,1H), 8.9 (s, 1H) 253 (R)-N-[2-Chloro-4-(3-fluoro- (CDCl₃) 1.75 (s, 3H),392 Ex phenylsulphanyl)phenyl]-2-hydroxy- 3.75 (s, 1H), 6.9-7.0 (m, 1972-methyl-3,3,3- 2H), 7.05 (d, 1H), 7.2-7.3 trifluoropropanamide (m, 1H),7.35 (dd, 1H), 7.45 (d, 1H), 8.4 (d, 1H), 9.0 (s, 1H) 254(R)-N-[2-Chloro-4-(4-sulphamoyl- (CDCl₃) 1.7 (s, 3H), 5.2 453 Exphenylsulphanyl)phenyl]-2- (s, 2H), 6.7 (s, 1H), 7.2- 210hydroxy-2-methyl-3,3,3- 7.25 (m, 2H), 7.4 (dd, trifluoropropanamide 1H),7.5 (d, 1H), 7.8 (d, 2H), 8.5 (d, 1H), 9.55 (s, 1H) 255(R)-N-{2-Chloro-4-[4-(guanidino- 1.6 (s, 3H), 6.75 (s, 4H), 495 Exsulphonyl)phenylsulphanyl] 7.35 (d, 2H), 7.5 (d, 1H), 210phenyl}-2-hydroxy-2-methyl- 7.6-7.7 (m, 3H), 7.9 (s,3,3,3-trifluoropropanamide 1H), 8.1 (d, 1H), 9.8 (s, 1H) 256(R)-N-[2-Chloro-4-(thiazol-2-yl- 1.62 (s, 3H), 7.64 (dd, 383 Exsulphanyl)phenyl]-2-hydroxy-2- 1H), 7.75 (d, 1H), 7.82 (d, (M + H)⁺ 197methyl-3,3,3- 1H), 7.87 (d, 1H), 8.12 (d, trifluoropropanamide 1H), 9.8(brs, 1H) 257 (R)-N-[2-Chloro-4-(1-methyl- 1.6 (s, 3H), 3.64 (s, 3H),380 Ex imidazol-2-ylsulphanyl)phenyl]-2- 7.1 (dd, 1H), 7.12 (d, 1H),(M + H)⁺ 197 hydroxy-2-methyl-3,3,3- 7.23 (d, 1H), 7.49 (d, 1H),trifluoropropanamide 7.86 (d, 1H), 9.7 (brs, 1H) 258(R)-N-[2-Chloro-4-(5-methyl- 1.63 (s, 3H), 2.66 (s, 3H), 396 Ex1,3,4-thiadiazol-2-ylsulphanyl) 7.7 (dd, 1H), 7.94 (d, 1H), 197phenyl]-2-hydroxy-2-methyl- 8.15 (d, 1H), 9.7 (brs, 1H)3,3,3-trifluoropropanamide 259 (R)-N-[2-Chloro-4-(pyrimidin-2- 1.64 (s,3H), 7.29 (t, 1H), 378 Ex ylsulphanyl)phenyl]-2-hydroxy-2- 7.62 (dd,1H), 7.83 (d, (M + H)⁺ 197 methyl-3,3,3- 1H), 7.9 (brs, 1H), 8.1 (d,trifluoropropanamide 1H), 8.63 (d, 2H), 9.8 (brs, 1H) 260(R)-N-[2-Chloro-4-(imidazol-2-yl- 1.6 (s, 3H), 7.2 (d, 1H), 364 Exsulphanyl)phenyl]-2-hydroxy-2- 7.3 (s, 2H), 7.75 (d, 1H), 197methyl-3,3,3- 7.87 (dd, 1H), 9.7 (brs, trifluoropropanamide 1H), 12.9(brs, 1H) 261 (R)-N-[2-Chloro-4-(benzothiazol- (CDCl₃) 1.8 (s, 3H), 3.9433 Ex 2-ylsulphanyl)phenyl]-2-hydroxy- (s, 1H), 7.25-7.3 (m, 1H), (M +H)⁺ 197 2-methyl-3,3,3- 7.4 (t, 1H), 7.7 (dd, 2H), trifluoropropanamide7.8 (dd, 1H), 7.9 (d, 1H), 8.5 (d, 1H), 9.2 (brs, 1H) 262(R)-N-[2-Chloro-4-(5-chloro- (CDCl₃) 1.75 (s, 3H), 2.7 467 Exbenzothiazol-2-ylsulphanyl) (s, 6H), 3.6 (s, 1H), 7.25 (M + H)⁺ 210phenyl]-2-hydroxy-2-methyl- (d, 2H), 7.45 (dd, 1H), 7.63,3,3-trifluoropropanamide (d, 1H), 7.7 (d, 2H), 8.45 (d, 1H), 9.1 (s,1H) 263 (R)-N-[2-Chloro-4-(N-methyl-4- 1.6 (s, 3H), 2.9 (s, 3H), 481 Exmesylaminophenylsulphanyl) 3.2 (s, 3H), 7.4 (m, 5H), 210phenyl]-2-hydroxy-2-methyl- 7.5 (s, 1H), 7.8 (s, 1H),3,3,3-trifluoropropanamide 8.0 (d, 1H) 264(R)-N-[2-Chloro-4-(2-nitrophenyl- 419 Ex sulphanyl)phenyl]-2-hydroxy-2-210 methyl-3,3,3- trifluoropropanamide   265^(1,2)(R)-N-[2-Chloro-4-(2,3-H-2-oxo- 1.6 (s, 3H), 3.4 (s, 3H), 445 Ex3-methylbenzoxazol-6- 7.2 (d, 1H), 7.4 (m, 3H), 210ylsulphanyl)phenyl]-2-hydroxy-2- 7.5 (s, 1H), 7.8 (s, 1H), methyl-3,3,3-7.9 (d, 1H), 9.7 (s, 1H) trifluoropropanamide   266^(1,3)(R)-N-[2-Chloro-4-(2-oxo-1,3- 458 Ex dimethylbenzimidazolidin-5- 210ylsulphanyl)phenyl]-2-hydroxy-2- methyl-3,3,3- trifluoropropanamide  267^(1,4) (R)-N-{2-Chloro-4-[4-(2-oxo- 1.6 (s, 3H), 2.0 (m, 2H), 457Ex pyrrolidin-1-yl)phenylsulphanyl] 2.7 (s, 1H), 2.9 (s, 1H), 210phenyl}-2-hydroxy-2-methyl- 3.8 (t, 2H), 7.2 (d, 1H),3,3,3-trifluoropropanamide 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (d, 2H), 7.9(d, 1H) 268 (R)-N-[2-Chloro-4-(1,2,3,4-H-1,3- 1.6 (s, 3H), 3.2 (s, 3H),486 Ex dimethyl-2,4-dioxoquinazolin-6- 3.5 (s, 3H), 7.3 (d, 1H), 210ylsulphanyl)phenyl]-2-hydroxy-2- 7.5 (m, 2H), 7.8 (d, 2H), andmethyl-3,3,3- 7.9 (s, 1H), 8.0 (d, 2H) Meth trifluoropropanamide 54 269(R)-N-{2-Chloro-4-(2H- 1.6 (s, 3H), 7.0 (m, 2H), 430 Exbenzimidazol-2-one-5- 7.1 (m, 3H), 7.7 (s, 1H), 210ylsulphanyl)phenyl}-2-hydroxy-2- 7.8 (d, 1H), 9.6 (s, 1H) andmethyl-3,3,3- 10.7 (s, 1H), 10.8 (s, 1H) Meth trifluoropropanamide 58270 (R)-N-{2-Chloro-4-(4- 1.6 (s, 3H), 2.6 (s, 3H), 416 Exacetylphenylsulphanyl)phenyl}-2- 7.3 (d, 2H), 7.5 (d, 1H), 210hydroxy-2-methyl-3,3,3- 7.7 (s, 1H), 7.9 (d, 2H), trifluoropropanamide8.1 (d, 1H) 271 (R)-N-{2-Chloro-4-(4-amino-3- 1.6 (s, 3H), 6.8 (d, 1H),433 Ex carboxyphenylsulphanyl)phenyl}- 7.0 (d, 1H), 7.1 (s, 1H), 2102-hydroxy-2-methyl-3,3,3- 7.4 (d, 1H), 7.7 (s, 1H), trifluoropropanamide7.8 (d, 1H), 7.9 (s, 1H), 9.6 (s, 1H) 272(R)-N-{2-Chloro-4-(4,5-diphenyl- (CDCl₃) 1.75 (s, 3H), 4.0 519 Ex2-oxazolylsulphanyl)phenyl}-2- (s, 1H), 7.25-7.4 (m, 6H), (M + H)⁺ 197hydroxy-2-methyl-3,3,3- 7.45-7.55 (m, 2H), 7.65 trifluoropropanamide(dd, 3H), 7.75 (d, 1H), 8.45 (d, 1H), 9.1 (brs, 1H) 273(R)-N-{2-Chloro-4-(1- (CDCl₃) 1.55 (t, 3H), 1.75 396 Exethyltetrazol-5-ylsulphanyl) (s, 3H), 4.40 (q, 2H), 4.55 (M + H)⁺ 197phenyl}-2-hydroxy-2-methyl- (s, 1H), 7.5 (dd, 1H), 7.653,3,3-trifluoropropanamide (d, 1H), 8.45 (d, 1H), 9.20 (brs, 1H) 274(R)-N-{2-Chloro-4-(4-iso-propyl- (CDCl₃) 1.55 (d, 6H), 1.8 457 Ex4,5-dihydro-1H-1,2,4-triazol-5- (s, 3H), 3.7 (brs, 1H), 4.8 (M + H)⁺ 197one-3-ylsulphanyl)phenyl}-2- (m, 1H), 7.9 (m, 1H),hydroxy-2-methyl-3,3,3- 8.05 (d, 1H), 8.8 (d, 1H), trifluoropropanamide9.45 (brs, 1H), 10.15 (brs, 1H) 275 (R)-N-{2-Chloro-4-(3-chloro-4- 1.75(s, 3H), 3.55 (s, 1H), 428 Ex fluorophenylsulphanyl)phenyl}-2- 7.1 (t,1H), 7.2-7.3 (m, (M + H)⁺ 197 hydroxy-2-methyl-3,3,3- 2H), 7.33-7.45 (m,2H), trifluoropropanamide 8.35 (d, 1H), 8.9 (brs, 1H) 276(R)-N-{2-Chloro-4-(3,4- (CDCl₃) 1.75 (s, 3H), 3.7 410 Exdifluorophenylsulphanyl)phenyl}- (s, 1H), 7.0-7.1 (m, 3H), 1972-hydroxy-2-methyl-3,3,3- 7.3 (dd, 1H), 7.4 (d, 1H), andtrifluoropropanamide 8.35 (d, 1H), 8.95 (brs, Meth 1H) 51 277(R)-N-{2-Chloro-4-(4- 1.25 (t, 3H), 1.4 (s, 3H), 438 Exethoxycarbonylimidazol-2- 4.2 (q, 2H), 7.25 (d, 1H), (M + H)⁺ 197ylsulphanyl)phenyl}-2-hydroxy-2- 7.45 (s, 1H), 7.8 (s, 1H),methyl-3,3,3- 7.90 (d, 1H), 8.0 (s, 1H), trifluoropropanamide 9.7 (s,1H), 13.35 (s, 1H)  278⁵ (R)-N-{2-Chloro-4-(4-{3-methyl- 1.62 (s, 3H),2.41 (s, 3H), 456 Ex 1,2,4-oxadiazol-5- 7.38 (d, 2H), 7.56 (dd, 210yl}phenylsulphanyl)phenyl}-2- 1H), 7.77 (d, 1H), 7.97hydroxy-2-methyl-3,3,3- (brs, 1H), 8.02 (d, 2H), trifluoropropanamide8.15 (d, 1H), 9.82 (brs, 1H)  279⁵ (R)-N-{2-Chloro-4-(4-{5-methyl- 1.6(s, 3H), 2.68 (s, 3H), 456 Ex 1,2,4-oxadiazol-3- 7.4 (d, 2H), 7.5 (dd,1H), 210 yl}phenylsulphanyl)phenyl}-2- 7.70 (d, 1H), 7.95 (m,hydroxy-2-methyl-3,3,3- 3H), 8.09 (d, 1H), 9.8 trifluoropropanamide(brs, 1H)

EXAMPLE 280

[0747](R)-N-[2-Chloro-4-(4-carboxyphenylsulphinyl)phenyl]2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0748] Oxone (1.47 g) as a solution in 1M sodium acetate solution (12ml) was added to a mixture of(R)-N-[2-chloro-4-(4-carboxyphenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 291) (1 g) in methanol (25 ml) and stirred for 2 hours. Thereaction mixture was filtered and the solid washed with water and driedunder vacuum to give the title compound as a solid (1.02 g) containing9% of the corresponding sulphone. NMR: 1.6 (s, 3H), 7.75 (d, 1H),7.8-7.9 (m, 3H), 7.95 (d, 1H), 8.0-8.05 (m, 3H), 8.15 (d, 1H), 9.8 (s,1H); MS (ESP⁻); 434.

EXAMPLES 281-283

[0749] Following the procedure of Example 280 (except that products werepurified by chromatography with ethyl acetate/hexane as eluent) andusing the appropriate starting materials the following compounds wereprepared. Ex Compound NMR MS SM 281 (R)-N-[2-Chloro-4-(5-methyl- (CDCl₃)1.76 (s, 3H), 2.81 (s, 412 Ex 258 1,3,4-thiadiazol-2-ylsulphinyl) 3H),3.9 and 3.91 (2xs, 1H), phenyl]-2-hydroxy-2-methyl- 7.7-7.78 (m, 1H),7.87-7.9 3,3,3-trifluoropropanamide (m, 1H), 8.69 (d, 1H), 9.23 (brs,1H) 282 (R)-N-[2-Chloro-4-(5-methyl- 1.62 (s, 3H), 2.84 (s, 3H), 428 Ex281 1,3,4-thiadiazol-2-ylsulphonyl) 8.12 (dd, 1H), 8.22 (d, 1H),phenyl]-2-hydroxy-2-methyl- 8.44 (d, 1H), 9.9 (brs, 1H)3,3,3-trifluoropropanamide 283 (R)-N-[2-Chloro-4-(4-ethenyl- (CDCl₃)1.76 (s, 3H), 3.05 (s, 356 Ex 419 sulphonyl)phenyl]-2-hydroxy-2- 1H),6.07 (d, 1H), 6.46 (d, methyl-3,3,3- 1H), 6.57-6.68 (dd, 1H),trifluoropropanamide 7.76-7.81 (m, 1H), 7.92 (s, 1H), 8.65 (d, 1H), 9.52(s, 1H)

EXAMPLE 284

[0750](R)-N-{2-Chloro-4-[4-(2-hydroxyethylsulphanyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0751] 2-Mercaptoethanol (0.358 ml) was added dropwise to anice/water-cooled suspension of sodium hydride (0.205 g) in NMP (6 ml).After effervescence had ceased, the cooling was removed and stirringcontinued a further 15 minutes.(R)-N-[2-Chloro-4-(4-fluorophenyl-sulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Method 69) (1.556 g) was added and the mixture was heated at 118° C.for 2 hours then cooled and poured onto saturated aqueous ammoniumchloride solution (60 ml). The mixture was extracted with ethyl acetate(2×200 ml) and the organic extracts were washed with brine (300 ml) thendried. Volatile material was removed by evaporation and the residue waspurified by chromatography eluting with 60% ethyl acetate/hexanes togive the title compound as a solid. NMR (CDCl₃): 1.74 (s, 31H), 1.91 (t,1H), 3.19 (t, 2H), 3.62 (s, 1H), 3.82 (q, 21H), 7.4 (d, 2H), 7.8 (d,2H), 7.83 (dd, 1H), 7.97 (d, 1H), 8.59 (d, 2H), 9.25 (brs, 1H); MS(ESP⁻); 482; EA: found: C, 44.6; H, 3.6; N, 2.7%; C₁₈H₁₇ClF₃NO₅S₂requires: C, 44.7; H, 3.5; N, 2.9%.

EXAMPLES 285-290

[0752] Following the procedure of Example 284 using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM  285¹ (R)-N-[2-Chloro-4-(pyrid-4- (CDCl₃ + DMSO-δ₆) 1.58 (s,515 Meth ylsulphanylphenylsulphonyl) 3H), 7.06 (d, 2H), 7.49 (brm, 69phenyl]-2-hydroxy-2-methyl- 3H), 7.75 (dd, 1H), 7.83 (d, 2H),3,3,3-trifluoropropanamide 7.9 (d, 1H), 8.35 (d, 2H), 8.57 (d, 1H), 9.73(brs, 1H) 286 (R)-N-{2-Chloro-4-[4-(N,N- (CDCl₃) 1.7 (s, 3H), 2.3 (s,6H), 511 Meth dimethylaminoethylsulphanyl) 2.6 (t, 2h), 3.1 (t, 2H),7.35 (d, (M + H)⁺ 69 phenylsulphonyl]phenyl}-2- 2H), 7.75-7.7 (m, 3H),7.95 (dd, hydroxy-2-methyl-3,3,3- 1H), 8.6 (d, 1H), 9.4 (brs, 1H)trifluoropropanamide 287 (R)-N-{2-Chloro-4-[4-(cyclo- 0.3 (q, 2H), 0.6(q, 2H), 1.05 (m, 492 Meth propylmethylsulphanyl)phenyl 1H), 1.7 (s,3H), 3.5 (d, 2H), 4.9 69 sulphonyl]phenyl}-2-hydroxy-2- (s, 1H), 7.35(d, 2H), 7.8 (d, 2H), methyl-3,3,3- 7.9 (m, 2H), 8.6 (d, 1H), 9.4trifluoropropanamide (brs, 1H) 288 (R)-N-{2-Chloro-4-[4-(N-methyl- 1.75(s, 3H), 2.8 (d, 3H), 3.70 (s, 509 Meth carbamoylmethylsulphanyl) 2H),4.7 (s, 1H), 6.65 (m, 1H), 69 phenylsulphonyl]phenyl}-2- 7.3 (d, 2H),7.7 (m, 3H), 7.95 hydroxy-2-methyl-3,3,3- (dd, 1H), 8.6 (d, 1H), 9.45(brs, trifluoropropanamide 1H) 289 (R)-N-{2-Chloro-4-[4-(N,N- 1.05 (t,6H), 1.8 (s, 3H), 2.6 (q, 537 Meth diethylaminoethylsulphanyl) 4H), 2.85(t, 2H), 3.1 (t, 2H), 7.3 69 phenylsulphonyl]phenyl}-2- (d, 2H),7.7-7.85 (m, 3H), 7.95 hydroxy-2-methyl-3,3,3- (dd, 1H), 8.6 (d, 1H),9.5 (brs, trifluoropropanamide 1H) 290 (R)-N-{2-Chloro-4-[2-(2- (CDCl₃)1.75 (s, 3H), 2.67 (brt, 482 Meth hydroxyethylsulphanyl)phenyl- 1H),3.12 (t, 2H), 3.65 (q, 2H), 63 sulphonyl]phenyl}-2-hydroxy-2- 3.75 (brs,1H), 7.4-7.47 (m, 1H), methyl-3,3,3- 7.5-7.6 (m, 2H), 7.86 (dd, 1H),trifluoropropanamide 8.07 (d, 1H), 8.26 (d, 1H), 8.6 (d, 1H), 9.3 (brs,1H)

EXAMPLE 291

[0753](R)-N-[2-Chloro-4-(4-carboxyphenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0754] A mixture of 4-mercaptobenzoic acid (0.308 g),(R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (0.786 g) and copper (I) oxide (0.143 g) in DMF (5 ml) wasstirred and heated under reflux for 1 hour. More 4-mercaptobenzoic acid(0.308 g) was added and heating was continued for a further 2 hours. Themixture was cooled, filtered, and the filter washed with DMF (5 ml). Thefiltrates were concentrated by evaporation and the residual solid wasextracted with boiling ethyl acetate (2×60 ml). The extracts wereabsorbed onto deactivated silica (silica deactivated by treatment with10% water) and purified by chromatography eluting with 5% methanol/ethylacetate to give the title compound (0.803 g) as a solid. NMR: 1.63 (s,3H), 7.31 (d, 2H), 7.5 (dd, 1H), 7.68 (d, 1H), 7.89 (d, 2H), 8.22 (d,1H), 9.8 (brs, 1H); MS (ESP⁻): 418; EA: found: C, 48.2; H, 3.1; N. 3.2%;CH₁₇H₁₃NClF₃O₄S requires C, 48.6; H, 3.1; N, 3.3%.

EXAMPLES 292-293

[0755] Following the procedure of Example 291 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS 292 (R)-N-[2-Chloro-4-{2-carboxy- 1.6 (s, 3H), 6.52 (d, 1H), 7.24(t, 418 phenylsulphanyl}phenyl]-2- 1H), 7.40 (t, 1H), 7.50-7.55 (m, 1H),hydroxy-2-methyl-3,3,3- 7.71 (s, 1H), 7.89-7.92 (m, 1H), 8.15trifluoropropanamide (d, 1H), 9.8 (s, 1H) 293(R)-N-{2-Chloro-4-(3-carboxy- 1.58 (s, 3H), 7.39 (d, 1H), 7.48-7.59 418phenylsulphanyl)phenyl}-2- (m, 3H), 7.83 (m, 3H), 8.01 (d, 1H),hydroxy-2-methyl-3,3,3- 9.72 (s, 1H) trifluoropropanamide

EXAMPLE 294

[0756](R)-N-{2-Chloro-4-[4-(N-2-hydroxyethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0757] A solution of 1,1′-carbonyldiimidazole (0.169 g) and(R)-N-[2-chloro-4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 121) (0.30 g) in DMF (1 ml)/ethyl acetate (9 ml) was heated at50° C. for 30 minutes. Ethanolamine (0.055 ml) was added and the mixturewas heated and stirred a further 17 hours. The mixture was cooled,diluted with ethyl acetate (50 ml), washed with dilute aqueoushydrochloric acid (25 ml), water (25 ml), saturated aqueous sodiumhydrogen carbonate solution (25 ml) and brine, then dried. Volatilematerial was removed by evaporation and the residue was purified bychromatography, eluting with 2.5% methanol/ethyl acetate to give thetitle compound (0.25 g) as a solid. NMR (CDCl₃+DMSO-δ₆): 1.58 (s, 3H),3.44 (m, 2H), 3.62 (m, 2H), 4.26 (t, 1H), 7.05 (s, 1H), 7.76 (dd, 1H),7.83-8.01 (m, 6H), 8.56 (d, 1H); 9.73 (brs, 1MS (ESP⁻): 495.

EXAMPLES 295-303

[0758] Following the procedure of Example 294 using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM 295 (R)-N-(2-Chloro-4-{4-[N′-(2-N,N- (CDCl₃ + DMSO-δ₆) 1.6 (s,520 Ex dimethylaminoethyl)carbamoyl] 3H), 2.26 (s, 6H), 2.47 (m, 2H),121 phenylsulphonyl}phenyl)-2- 3.43 (m, 2H), 7.48 (s, 1H), 7.75hydroxy-2-methyl-3,3,3- (m, 1H), 7.82-7.98 (m, 5H), trifluoropropanamide8.54 (d, 1H), 9.73 (brs, 1H) 296 (R)-N-{2-Chloro-4-[4-(morpholino-(DMSO-δ₆ + AcOH-δ₄) 1.62 (s, 519 Ex carbonyl)phenylsulphonyl]phenyl}-3H), 3.4 (s, 4H), 3.58 (m, 4H), 121 2-hydroxy-2-methyl-3,3,3- 7.6 (d,2H), 7.9-8.1 (m, 4H), trifluoropropanamide 8.35 (d, 1H) 297(R)-N-{2-Chloro-4-[4-(4-methyl- (DMSO-δ₆ + AcOH-δ₄) 1.6 (s, 532 Expiperazin-1-ylcarbonyl)phenyl- 3H), 2.35 (s, 1H), 2.68 (m, 4H), 121sulphonyl]phenyl}-2-hydroxy-2- 3.5 (brs, 4H), 7.58 (d, 2H), 7.85-methyl-3,3,3-trifluoropropanamide 8.05 (m, 4H), 8.38 (d, 1H) 298(R)-N-{2-Chloro-4-[4-(pyrrolidin- 1.58 (s, 3H), 1.7-1.89 (m, 4H), 503 Ex1-ylcarbonyl)phenylsulphonyl] 3.23 (m, 2H), 3.41 (m, 2H), 7.7 121phenyl}-2-hydroxy-2-methyl-3,3,3- (d, 2H), 8.0 (m, 4H), 8.18 (s,trifluoropropanamide 1H), 8.3 (d, 1H), 9.88 (brs, 1H) 299(R)-N-(2-Chloro-4-{4-[N-(2- 1.57 (s, 3H), 3.22 (m, 2H), 3.4 507 Exmethoxyethyl)carbamoyl]phenyl- (m, 2H), 7.9-8.02 (m, 4H), 8.08 121sulphonyl}phenyl)-2-hydroxy-2- (d, 2H), 8.14 (s, 1H), 8.3 (d,methyl-3,3,3-trifluoropropanamide 1H), 8.72 (m, 1H), 9.9 (brs, 1H) 300(R)-N-{2-Chloro-4-[4- 1.59 (s, 3H), 2.52 (brs, 2H), 535 Ex(thiomorpholinocarbonyl)phenyl- 2.64 (brs, 2H), 3.42 (brs, 2H), 121sulphonyl]phenyl}-2-hydroxy-2- 3.81 (brs, 2H), 7.72 d, 2H),methyl-3,3,3-trifluoropropanamide 7.96-8.1 (m, 4H), 8.17 (s, 1H), 8.31(d, 1H), 9.89 (brs, 1H) 301 (R)-N-{2-Chloro-4-[4-(thiazolidin- 1.59 (s,3H), 2.96 (brs, 1H), 521 Ex 3-ylcarbonyl)phenylsulphonyl] 3.03 (brs,1H), 3.6 (brs, 1H), 3.8 121 phenyl}-2-hydroxy-2-methyl-3,3,3- (brs, 1H),4.42 (brs, 1H), 4.62 trifluoropropanamide (brs, 1H), 7.76 (d, 2H), 8.02(m, 2H), 8.06 (d, 2H), 8.18 (s, 1H), 8.32 (d, 1H), 9.9 (brs, 1H) 302(R)-N-(2-Chloro-4-{2-[N-(2- 1.65 (s, 3H), 3.3-3.5 (m, 4H), 493 Exhydroxyethyl)carbamoyl]phenyl- 4.7 (t, 1H), 7.55 (d, 1H), 7.7- 125sulphonyl}phenyl)-2-hydroxy-2- 7.82 (m, 2H), 8.05-8.1 (m, 2H),methyl-3,3,3-trifluoropropanamide 8.1 (dd, 1H), 8.28 (d, 1H), 8.34 (d,1H), 8.55 (brt, 1H), 9.97 (brs, 1H) 303 (R)-N-(2-Chloro-4-{4-[N-(2-1.0-1.1 (m, 3H), 1.6 (s, 3H), 493 Ex hydroxy-1-methylethyl)carbamoyl]3.3-3.4 (m, 1H), 4.6-4.7 (m, (M + H)⁺ 280 phenyl-sulphinyl}phenyl)-2-2H), 6.8 (d, 1H), 7.3 (d, 1H), 7.7 hydroxy-2-methyl-3,3,3- (d, 1H),7.7-7.8 (m, 1H), 7.9- trifluoropropanamide 7.95 (m, 3H), 8.0-8.2 (m,3H), 9.8 (s, 1H)

EXAMPLE 304

[0759](R)-N-[2-Chloro-4-(4-anilinocarbonylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0760] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.195 g) was added to a solution of 4-(dimethylamino)pyridine (0.25 g),(R)-N-[2-chloro-4-(4-carboxyphenyl-sulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 121) (0.317 g) and aniline (0.075 ml) in DCM (30 ml) and themixture was stirred for 6 days. Solvent was then removed by evaporationand the residue was partitioned between ethyl acetate (50 ml) and diluteaqueous hydrochloric acid (25 ml). The aqueous layer was furtherextracted with ethyl acetate (50 ml). The organic extracts werecombined, washed with brine and dried. Volatile material was removed byevaporation and the residue was purified by chromatography eluting with40% ethyl acetate/hexane to give the title compound (0.179 g) as asolid. NMR (CDCl₃+DMSO-δ₆): 1.59 (s, 3H), 7.03 (t, 1H), 7.25 (t, 2H),7.48 (brs, 1H), 7.64 (d, 2H), 7.78 (dd, 1H), 7.92 (m, 3H), 8.06 (d, 2H),8.56 (d, 1H), 9.72 (s, 1H), 9.9 (s, 1H);

[0761] MS (ESP⁻): 525.

EXAMPLES 305-306

[0762] Following the procedure of Example 304 and using Example 125 asthe starting material the following compounds were prepared. Ex CompoundNMR MS 305 (R)-N-{2-Chloro-4-[2-(pyrrolidin- 1.59 (s, 3H), 1.76-1.89 (m,4H), 3.02 (t, 503 1-ylcarbonyl)phenylsulphonyl] 2H), 3.47 (t, 2H),7.44-7.47 (m, 1H), phenyl}-2-hydroxy-2-methyl-3,3,3- 7.63-7.68 (m, 1H),7.97-8.0 (m, 1H), trifluoropropananiide 8.12 (d, 1H), 8.18 (s, 1H), 8.24(d, 1H)  306¹ (R)-N-(2-Chloro-4-{2-[N′-(2-N,N- (DMSO-δ₆ + AcOH-δ₄): 1.56(s, 3H), 520 dimethylaminoethyl) 2.85 (s, 6H), 3.30 (t, 2H), 3.62 (t,2H), carbamoyl]phenylsulphonyl} 7.52 (d, 1H), 7.64-7.73 (m, 2H), 7.96-phenyl)-2-hydroxy-2-methyl-3,3,3- 8.00 (m, 1H), 8.07-8.1 (m, 1H), 8.15(s, trifluoropropanamide hydrochloride 1H), 8.15 (d, 1H)

EXAMPLE 307

[0763](R)-N-[2-Chloro-4-(thien-2-ylmethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0764] N-Methylmorpholine-N-oxide (0.75 g) and 4A molecular sieves(0.215 g) were added to a solution of(R)-N-[2-chloro-4-(thien-2-ylmethylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 418) (0.085 g) in deoxygenated acetonitrile (10 ml) and themixture was stirred for 5 minutes. Tetrapropylammonium perruthenate(0.037 g) was then added and the mixture was heated at 45° C. for 2.5hours then cooled. Ethyl acetate (50 ml) was added, the mixture filteredand volatile material was removed by evaporation. The residue waspurified by chromatography on a silica gel Mega Bond Elut column elutingwith 20-50% ethyl acetate/iso-hexane to give the title compound (0.034g) as a yellow solid. NMR (CDCl₃): 1.61 s, 3H), 5.05 (s, 2H), 6.94 (s,1H), 6.98-7.0 (m, 1H), 7.53 (d, 1H), 7.91 (s, 1H), 8.28 (d, 1H), 9.94(s, 1H); MS (ESP⁻): 426.

EXAMPLE 308

[0765](R)-N-{2-Fluoro-4-[4-(N-methylcarbamoylmethylsulphanyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0766](R)-N-[2-Fluoro-4-(4-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(0.65 g) (Method 71) was added to a deoxygenated mixture ofmercaptoacetamide (0.14 ml) and sodium methoxide (0.08 g) in anhydrousNMP (2 ml). The reaction mixture was heated to 140° C. for 6 hours thencooled, diluted with ether (80 ml), washed with saturated aqueousammonium chloride (100 ml) and dried. Volatile material was removed byevaporation and the residue was purified by chromatography on a silicagel Mega Bond Elut column eluting with 10-60% ethyl acetate/hexane togive the title compound (0.46 g) as a gum. NMR (CDCl₃) 1.75 (s, 3H), 2.8(d, 3H), 3.69 (s, 2H), 7.3 (d, 2H), 7.69-7.75 (m, 2H), 7.83 (d, 1H),8.8-8.85 (m, 1H), 9.0 (s 1H); MS (ESP⁻): 493.

EXAMPLES 309-311

[0767] Following the procedure of Example 308 using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM 309 (R)-N-{2-Fluoro-4-[4-(2- (CDCl₃) 1.73 (s, 3H), 3.18 (t,2H), 466 Meth hydroxyethylsulphanyl)phenyl 3.52 (s, 1H), 3.8-3.84 (m,2H), 7.39 71 sulphonyl]phenyl}-2-hydroxy- (d, 2H), 7.65-7.73 (m, 1H),7.78 (d, 2-methyl-3,3,3- 1H), 8.5-8.55 (m, 1H), 8.84 (s, 1H)trifluoropropanamide 310 (R)-N-{2-Chloro-4-[3-chloro- (CDCl₃) 1.75 (s,3H), 1.95 (t, 1H), 516 Meth 4-(2-hydroxyethylsulphanyl)- 3.2 (t, 2H),3.75 (s, 1H), 3.9 (q, 2H), 72 phenylsulphonyl]phenyl}-2- 7.35 (d, 1H),7.7 (dd, 1H), 7.8-7.9 hydroxy-2-methyl-3,3,3- (m, 2H), 7.95 (d, 1H),8.60 (d, 1H), trifluoropropanamide 9.3 (s, 1H) 311(R)-N-{2-Chloro-4-[3-fluoro- 1.6 (s, 3H), 3.15 (t, 2H), 3.6 (q, 2H), 500Meth 4-(2-hydroxyethylsulphanyl)- 5.0 (t, 1H), 7.65 (t, 1H), 7.75 (dd,66 phenylsulphonyl]phenyl}-2- 1H), 7.85 (dd, 1H), 7.90-8.1 (m,hydroxy-2-methyl-3,3,3- 2H), 8.2 (d, 1H), 8.3 (d, 1H), 9.9trifluoropropanamide (brs, 1H)

EXAMPLE 312

[0768](R)-N-[2-Chloro-4-(N,N-dimethylaminoethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0769] A 2M solution of dimethylamine (0.06 ml) in anhydrous methanolwas added to a deoxygenated solution of(R)-N-[2-chloro-4-(ethenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 283) (0.044 g) in anhydrous THF (1 ml). The mixture was allowedto stir at ambient temperature under argon for 2 hours then volatilematerial was removed by evaporation to give the title compound (in 89%yield) as a solid. NMR: 1.69 (s, 3H), 2.65 (s, 6H), 2.55 (t, 2H), 3.55(t, 2H), 7.9 (d, 1H), 8.08 (s, 1H), 8.34 (d, 1H); MS (ESP⁻): 403.

EXAMPLE 313

[0770](R)-N-[2-Ethenyl-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0771] Tributylvinyltin (0.28 ml) was added to a deoxygenated suspensionof(R)-N-[2-bromo-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 140) (0.50 g) and tris(dibenzylideneacetone)dipalladium(O)(0.05 g) in anhydrous toluene (10 ml). The mixture was heated underreflux with stirring. After 14 hours a further portion oftris(dibenzylideneacetone)dipalladium(0) (0.05 g) and tributylvinyltin(0.28 ml) was added and heating was continued for a further 7 hours. Thereaction mixture was allowed to cool and volatile materials were removedby evaporation. The residue was purified on a silica gel Mega Bond Elutcolumn eluting with 5-50% ethyl acetate/hexane to give the titlecompound (0.146 g) as a solid. NMR (CDCl₃) 1.74 (s, 3H), 3.06 (s, 3H),5.65-5.82 (dd, 2H), 6.67-6.77 (dd, 1H), 7.86-7.89 (dd, 1H), 7.95 (s,1H), 8.06-8.16 (m, 4H), 8.35 (d, 1H), 8.79 (s, 1H); MS (ESP⁻): 477.

EXAMPLE 314

[0772](R)-N-[2-Chloro-4-(carboxymethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0773] Sodium hydroxide (2.5 ml of a 2M aqueous solution) was added to astirred solution of(R)-N-[2-chloro-4-(methoxycarbonylmethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 142) (0.36 g) in methanol (6 ml) and the mixture was stirredfor 1 hour. Hydrochloric acid (3 ml of a 2M aqueous solution) was addedand volatile material was removed by evaporation. Ethyl acetate (80 ml)was added and the mixture washed with brine (50 ml), dried and volatilematerial removed by evaporation. The residue was dissolved in DCM (50ml), washed with saturated sodium hydrogen, carbonate solution (100 ml).The aqueous layer was treated with hydrochloric acid (25 ml, 10% v/v)and extracted into ethyl acetate (2×100 ml) and dried. Volatile materialwas removed by evaporation to give the title compound (0.28 g) as afoam. NMR: 1.62 (s, 3H), 4.57 (s, 2H), 7.9 (d, 2H), 8.02 (s, 1H), 8.06(s, 1H), 8.32 (d, 1H). 9.92 (s, 1H); MS (ESP⁻): 388.

EXAMPLE 315

[0774](R)-N-[2-Chloro-4-(N,N-dimethylaminopropylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0775] A solution of potassium permanganate (0.12 g) in water (8 ml) wasadded to a stirred solution of(R)-N-[2-chloro4-(3-N,N-dimethylaminopropylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 404) (0.198 g) in glacial acetic acid (10 ml). The reactionmixture was stirred for 30 minutes then sodium sulphite was added untilthe reaction mixture became clear and colourless. Ethyl acetate (100 ml)was added and the mixture was washed with brine (2×50 ml), saturatedaqueous sodium hydrogencarbonate solution (150 ml) and dried. Volatilematerial was removed by evaporation and the residue purified bychromatography on a silica gel Mega Bond Elut column eluting with 0-15%methanol/ethyl acetate to give the title compound (in 33% yield) as asolid. NMR: 1.61 (s, 3H), 1.61-1.68 (m, 2H), 2.05 (s, 6H), 2.23 (t, 2H),3.28-3.36 (m, 2H), 7.89 (d, 1H), 8.04 (s, 1H), 8.33 (d, 1H); MS (ESP⁻):415.

EXAMPLES 316-326

[0776] Following the procedure of Example 315 and using the appropriatestarting materials following compounds were prepared. Ex Compound NMR MSSM 316 (R)-N-[2-Chloro-4-(benzo- (CDCl₃) 1.75 (s, 3H), 3.4 (brs, 1H),465 Ex 261 thiazol-2-ylsulphonyl)phenyl]- 7.5-7.6 (m, 2H), 7.95 (dd,1H), 8.1 (M + H)⁺ 2-hydroxy-2-methyl-3,3,3- (dd, 1H), 8.15 (dd, 1H), 8.2(d, 1H), trifluoropropanamide 8.7 (d, 1H), 9.3 (bis, 1H) 317(R)-N-[2-Chloro-4-(5-chloro- (CDCl₃) 1.75 (s, 3H), 3.4 (s, 1H), 498 Ex262 benzothiazol-2-ylsulphonyl) 7.5-7.55 (m, 2H), 8.0-8.15 (m, 2H), (M +H)⁺ phenyl]-2-hydroxy-2-methyl- 8.2 (d, 1H), 8.7 (d, 1H), 9.35 (brs,3,3,3-trifluoropropanamide 1H) 318 (R)-N-[2-Chloro-4-(4-{N-[5- 1.65 (s,3H), 2.25 (s, 3H), 5.4 (brs, 530 Ex 239 methylpyrazol-3-yl] 2H), 5.6 (s,1H), 7.95-8.05 (m, 2H), (M + H)⁺ carbamoyl}phenylsulphonyl) 8.1-8.2 (m,5H), 8.3 (d, 1H), 9.90 (s, phenyl]-2-hydroxy-2-rnethyl- 1H)3,3,3-trifluoropropanamide 319 (R)-N-[2-Chloro-4-(4-{N- 1.6 (s, 3H), 7.0(s, 1H), 8.0 (d, 2H), 516 Ex 240 [isoxazol-3-yl]carbamoyl} 8.05 (d, 1H),8.1-8.15 (m, 3H), 8.2 phenylsulphonyl)phenyl]-2- (d, 1H), 8.3 (d, 1H),8.85 (d, 1H), hydroxy-2-methyl-3,3,3- 9.90 (s, 1H), 11.65 (s, 1H)trifluoropropanamide 320 (R)-N-[2-Chloro-4-(4- 1.25 (t, 3H), 1.6 (s,3H), 4.25 (q, 470 Ex 277 ethoxycarbonylimidazol-2- 2H), 8.0 (dd, 1H),8.1 (s, 1H), 8.15 (M + H)⁺ ylsulphonyl)phenyl]-2- (d, 2H), 8.4 (d, 1H),9.95 (s, 1H), hydroxy-2-methyl-3,3,3- 11.95 and 14.55 (2xbrs, 1H)trifluoropropanamide 321 (R)-N-{2-Chloro-4-[4-(1′,1′- 1.6 (s, 3H), 3.12(brs, 4H), 3.9 (brs, 539 Ex 82 dioxothiomorpholino)phenyl 4H), 7.14 (d,2H), 7.78 (d, 2H), 7.92 sulphonyl]phenyl}-2-hydroxy- (dd, 1H), 8.06 (d,1H), 8.22 (d, 1H), 2-methyl-3,3,3- 9.9 (brs, 1H) trifluoropropanamide322 (R)-N-{2-Chloro-4-(4-{3- 1.6 (s, 3H), 2.43 (s, 3H), 8.04 (dd, 488 Ex278 methyl-1,2,4-oxadiazol-5- 2H), 8.20-8.25 (m, 3H), 8.27-8.37yl}phenylsulphonyl)phenyl}- (m, 3H), 9.94 (brs, 1H)2-hydroxy-2-methyl-3,3,3- trifluoropropanamide 323(R)-N-{2-Chloro-4-(4-{5- 1.61 (s, 3H), 2.69 (s, 3H), 8.02 (dd, 488 Ex279 methyl-1,2,4-oxadiazol-3- 1H) : 8.15-8.25 (m, 5H), 8.34 (d,yl}phenylsulphonyl)phenyl}- 1H), 9.9 (brs, 1H) 2-hydroxy-2-methyl-3,3,3-trifluoropropanamide 324 (R)-N-{2-Chloro-4-(4- (CDCl₃) 1.76 (s, 3H),3.82 (s, 1H), 484 Ex 203 pyrimidin-2-ylphenyl- 7.28 (m, 1H), 7.9 (dd,1H), 8.0-8.08 sulphonyl)phenyl}-2-hydroxy- (m, 3H), 8.58-8.67 (m, 3H),8.85 (d, 2-methyl-3,3,3- 2H), 9.3 (brs, 1H) trifluoropropanamide 325(R)-N-{2-Chloro-4-(3- (DMSO-δ₆ + AcOD-d₄): 1.59 (s, 3H), 429 Ex 406acetamidopropylsulphonyl) 1.61-1.69 (m, 2H), 1.73 (s, 3H),phenyl}-2-hydroxy-2-methyl- 3.05 (t, 2H), 3.25-3.31 (m, 2H),3,3,3-trifluoropropanamide 7.82-7.86 (m, 1H), 7.97 (s, 1H), 8.39 (s, 1H)326 (R)-N-{2-Chloro-4-([5- 1.34 (t, 3H), 1.59 (s, 3H), 4.37 (q, 479 Ex202 ethoxycarbonyl-3- 2H), 8.07 (s, 1H), 8.12 (d, 1H),pyridyl]sulphonyl)phenyl}-2- 8.33-8.36 (m, 2H), 8.69 (s, 1H),hydroxy-2-methyl-3,3,3- 9.30 (s, 1H), 9.43 (s, 1H), 9.93 (s,trifluoropropanamide 1H)

EXAMPLE 327

[0777](R)-N-[2-Chloro-4-(ethylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0778] Copper (I) chloride (0.5 g) and sodium ethanethiolate (0.54 g)were added sequentially to a deoxygenated solution of(R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (2.0 g) in quinoline (6 ml) and pyridine (1.5 ml). Themixture was heated to 200° C. under argon for 18 hours, cooled dissolvedin ethyl acetate (200 ml), washed with dilute aqueous hydrochloric acid(2×100 ml) and brine (2×50 ml) and then dried. Volatile material wasremoved by evaporation and the residue was purified by chromatography onsilica gel eluting with 10-40% ethyl acetate/iso-hexane to give thetitle compound as a gum (1.4 g). NMR (CDCl₃): 1.29 (t, 3H), 1.57 (s,3H), 2.91 (q, 2H), 3.69 (s 1H), 7.24 (d, 1H), 7.35 (s, 1H), 8.24 (d,1H), 8.77 (s, 1H); MS (ESP⁻): 326.

EXAMPLE 328

[0779] Following the procedure of Example 327 and using the appropriatestarting materials the following compound was prepared. Ex Compound NMR(CDCl₃) MS 328¹ (R)-N-[2-Chloro-4-(3-hydroxy- 1.74 (s, 3H), 1.86-1.92(m, 2H), 3.00-3.05 356 propylsulphanyl)phenyl]-2- (t, 2H), 3.75-3.83 (t,2H), 7.27 (d, 1H), hydroxy-2-methyl-3,3,3- 7.39 (s, 1H), 8.28 (d, 1H),8.83 (brs, 1H). trifluoropropanamide

EXAMPLE 329

[0780](R)-N-{2-Chloro-4-[4-(N-methylcarbamoylmethylsulphinyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropronanamide

[0781] A sample of(R)-N-{2-chloro-4-[4-(N-methylcarbamoylmethylsulphanyl)phenyl-sulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 288) was left standing open to air for approximately one weekthen purified by chromatography on silica gel eluting with 0-5%methanol/DCM to give (in 10% yield) the title compound as a solid.

[0782] NMR (CDCl₃): 1.7 (s, 3H), 2.8 (d, 3H), 3.4 (d, 1H), 3.75 (d, 1H),3.9 (s, 1H), 6.6 (m, 1H), 7.75 (d, 2H), 7.85 (m, 1H), 8.0 (dd, 1H), 8.1(d, 2H), 8.65 (d, 1H), 9.35 (brs, 1H); MS (ESP⁻): 525.

EXAMPLE 330

[0783] By the method of Example 329 using the appropriate startingmaterial the following compound was prepared. Ex Compound NMR MS SM 330¹(R)-N-[2-Chloro-4-(4- (CDCl₃) 0.3 (m, 2H), 0.65 (m, 2H), 0.9- 508 Ex 287cyclopropylmethylsulphinyl- 1.0 (m, 1H), 1.7 (s, 3H), 2.65-2.8 (m,phenylsulphonyl)phenyl]- 1H), 2.8-2.95 (m, 1H), 5.64 (d, 1H),2-hydroxy-2-methyl-3,3,3- 7.7-7.9 (m, 3H), 7.95 (m, 1H), 8.05-8.1trifluoropropanamide (d, 2H), 8.65 (d, 1H), 9.6 (brs, 1H)

EXAMPLE 331

[0784](R)-N-[2-Chloro-4-(3-nitrophenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0785] A mixture of 3-nitrophenyldisulphide (0.176 g) and(R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (0.15 g) in diphenyl ether (5 ml) was heated and stirredat 250° C. for 2 days. The reaction mixture was cooled, diluted withiso-hexane (5 ml) and purified by chromatography eluting with 10-100%DCM/hexane to give the title compound (0.05 g) as an oil. NMR (CDCl₃):1.8 (s, 3H), 3.6 (s, 1H), 7.4-7.55 (m, 4H), 8.1 (brs, 2H), 8.45 (d, 1H),9.05 (brs, 1H); MS (ESP⁺): 421 (M+H)⁺.

EXAMPLE 332

[0786](R)-N-[2-Chloro-4-(N-phenylcarbamoyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0787] A mixture of(R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (0.35 g), aniline (0.117 ml), tributylamine (0.232 ml) anddichlorobis-(triphenylphosphine)palladium(II) (0.009 g) was heated at100° C. under an atmosphere of carbon monoxide for 4 hours. Ethylacetate (10 ml) was added and the mixture was washed with water andbrine then was dried. Volatile material was removed by evaporation andthe residue was purified by chromatography on a silica gel Mega BondElut column eluting with 5-50% ethyl acetate/hexane followed by passingthrough a Varian Isolute SCX column to give the title compound (0.17 g)as a solid. NMR: 1.6 (s, 3H), 7.1 (t, 1H), 7.35 (t, 2H), 7.75 (d, 2H),7.92 (s, 1H), 7.98 (dd, 1H), 8.12 (s, 1H), 8.2 (d, 1H), 9.8 (s, 1H),10,26 (brs, 1H); MS (ESP−): 386.

EXAMPLES 333-334

[0788] By the method of Example 332 using Example 197 as the startingmaterials the following compounds were prepared. Ex Compound NMR MS 333(R)-N-[2-Chloro-4-(N-n- 0.88 (t, 3H), 1.3 (m, 2H), 1.48 (m, 365butylcarbamoyl)phenyl]-2-hydroxy-2- 2H), 1.6 (s, 3H), 3.2 (t, 2H), 7.83(dd, methyl-3,3,3-trifluoropropanamide 1H), 7.9 (s, 1H), 8.0 (d, 1H),8.12 (d, 1H), 8.5 (brt, 1H), 9.8 (s, 1H) 334(R)-N-[2-Chloro-4-(piperidin-1- (DMSO-δ₆ + AcOH-δ₄, at 373K): 1.5 377ylcarbonyl)phenyl]-2-hydroxy-2- (m, 4H), 1.6 (m, 4H), 3.44 (m, 4H),methyl-3,3,3-trifluoropropanamide 7.35 (d, 1H), 7.46 (s, 1H), 8.15 (d,1H)

EXAMPLE 335

[0789] 3-Hydroxy-3-methyl-1-(2-fluoro-4-phenylsulphonylphenyl)but-1-yne

[0790] Bis(triphenylphosphine)palladium(II) chloride (0.034 g) was addedto a solution of 2-methyl-3-butyn-2-ol (0.11 ml) and2-fluoro-4-phenylsulphonylbromobenzene (Method 1) (0.548 g) intriethylamine (3 ml) and DMF (1 ml) and the mixture was heated at 70° C.for 18 hours. The mixture was poured into water (50 ml) and extractedwith ethyl acetate (2×50 ml). The extracts were washed with brine thendried. Volatile material was removed by evaporation and the residue waspurified by chromatography on a silica gel Mega Bond Elut column elutingwith 40-100% ethyl acetate/hexane then triturated with hexane to givethe title compound (0.112 g) as a solid. NMR (CDCl₃): 1.6 (s, 6H),7.5-7.7 (m, 6H), 7.9 (d, 2H); MS (EI): 318 (M⁺).

EXAMPLE 336

[0791](R)-N-{2-Chloro-4-[2-(iso-pronylaminocarbonyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0792] N-Methylmorpholine (1.22 ml) ando-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.092 g) were added to a solution of(R)-N-[2-chloro4-(2-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 125) (0.10 g) and 2-propylamine (0.024 ml) in DCM (20 ml) at 0°C. The reaction mixture was stirred at this temperature for 30 minutesthen allowed to warm to room temperature. stirred for a further 3 hoursthen evaporated to dryness. The residue was purified by chromatographyon a silica gel Mega Bond Elut column eluting with 50% ethylacetate/hexane then triturated with ether/hexane to give the titlecompound (0.05 g) as a solid. NMR (CDCl₃): 1.3 (d, 6H), 1.6 (s, 3H),4.2-4.32 (m, 1H), 5.8 (brd, 1H), 7.4 (d, 1H), 7.5-7.7 (m, 3H), 7.9 (dd,1H),8.05-8.13 (m, 2H), 8.6 (d, 1H), 9.3 (brs, 1H); MS (ESP⁻): 491.

EXAMPLES 337-349

[0793] The aniline starting material was acylated with an appropriateacid chloride by the procedure of Method 17 or sulphonylated with anappropriate sulphonyl chloride by the procedure of Method 26 thenhydrolysed by the procedure of Example 171. There were thus obtained thefollowing compounds. Ex Compound NMR MS SM 337(R)-N-[2-Chloro-4-(4-benzoyl- 1.6 (s, 3H), 7.2 (d, 1H), 7.3 493 Methaminophenylsulphanyl)phenyl]-2- (s, 1H), 7.5 (m, 5H), 7.9 12hydroxy-2-methyl-3,3,3- (m, 6H), 10.4 (s,1H) trifluoropropanamide 338(R)-N-[2-Chloro-4-(4-t-butyl- 1.2 (s, 9H), 1.6 (s, 3H), 7.2 473 Methcarbonylaminophenylsulphanyl) (d, 1H), 7.3 (s, 1H), 7.4 (d, 12phenyl]-2-hydroxy-2-methyl-3,3,3- 2H), 7.7 (d, 2H), 7.9 (d,trifluoropropanamide 1H), 9.3 (s, 1H), 9.7 (s, 1H) 339(R)-N-{2-Chloro-4-[4-(4-chloro- 1.6 (s, 3H), 7.2 (d, 1H), 7.3 527 Methbenzoylamino)phenylsulphanyl] (s, 1H), 7.4 (d, 2H), 7.6 (d, 12phenyl}-2-hydroxy-2-methyl-3,3,3- 2H), 7.9 (m, 6H), 9.7 (s,trifluoropropanamide 1H), 10.4 (s, 1H) 340(R)-N-{2-Chloro-4-[4-(2-methoxy- 1.5 (s, 3H), 3.3 (s, 3H), 4.0 461 Methacetylamino)phenylsulphanyl] (s, 2H), 7.2 (d, 1H), 7.3 (s, 12phenyl}-2-hydroxy-2-methyl-3,3,3- 1H), 7.4 (d, 2H), 7.7 (d,trifluoropropanamide 3H), 7.9 (d, 1H), 9.6 (s, 1H), 9.9 (s, 1H) 341(R)-N-{2-Chloro-4-[4-(pyrid-3- 1.6 (s, 3H), 7.2 (d, 1H), 7.3 494 Methylcarbonylamino)phenylsulphanyl] (s, 1H), 7.5 (d, 2H), 7.7 (s, 12phenyl}-2-hydroxy-2-methyl-3,3,3- 1H), 7.8 (m, 4H), 7.9 (d,trifluoropropanamide 1H), 8.8 (d, 2H), 9.7 (s, 1H), 10.6 (s, 1H) 342(R)-N-[2-Chloro-4-(2-mesylamino- 1.6 (s, 3H), 3.0 (s, 3H), 7.4 467 Methphenylsulphanyl)phenyl]-2-hydroxy- (m, 7H), 7.8 (s, 1H), 8.0 362-methyl-3,3,3-trifluoropropanamide (d, 1H), 9.7 (s, 1H) 343(R)-N-[2-Chloro-4-(2-acetylamino- 1.6 (s, 3H), 2.0 (s, 3H), 7.2 431 Methphenylsulphanyl)phenyl]-2-hydroxy- (m, 2H), 7.3 (m, 3H), 7.6 362-methyl-3,3,3-trifluoropropanamide (d, 1H), 7.8 (s, 1H), 7.9 (d, 1H),9.5 (s, 1H), 9.7 (s, 1H) 344 (R)-N-[2-Chloro-4-(4-mesylamino- 1.6 (s,3H), 3.0 (s, 3H), 7.2 467 Meth phenylsulphanyl)phenyl]-2-hydroxy- (m,3H), 7.3 (s, 1H), 7.2 12 2-methyl-3,3,3-trifluoropropanamide (d, 2H),7.8 (s, 1H), 7.9 (d, 1H), 9.7 (s, 1H), 9.9 (s, 1H) 345(R)-N-{2-Chloro-4-[4-(phenyl- 1.6 (s, 3H), 7.1 (t, 3H), 7.2 529 Methsulphonylamino)phenyl- (s, 1H), 7.3 (d, 2H), 7.6 12sulphanyl]phenyl}-2-hydroxy-2- (m, 3H), 7.8 (m, 3H), 7.9methyl-3,3,3-trifluoropropanamide (d, 1H), 9.7 (s, 1H), 10.5 (s, 1H)346¹ (R)-N-{2-Chloro-4-[4-(ethenyl- 1.6 (s, 3H), 6.1 (m, 2H), 479 Methsulphonylamino)phenylsulphanyl] 7.8 (q, 1H), 7.2 (m, 3H), 12phenyl}-2-hydroxy-2-methyl-3,3,3- 7.4 (m, 3H), 7.8 (s, 1H),trifluoropropanamide 7.9 (d, 1H), 9.7 (s, 1H), 10.25 (s, 1H) 347(R)-N-[2-Chloro-4-(3-mesylamino- 1.6 (s, 3H), 3.0 (s, 3H), 7.0 467 Methphenylsulphanyl)phenyl]-2-hydroxy- (d, 1H), 7.1 (d, 2H), 7.3 372-methyl-3,3,3-trifluoropropanamide (m, 2H), 7.5 (s, 1H), 7.8 (s, 1H),8.0 (s, 1H), 9.7 (s, 1H), 9.8 (s, 1H). 348(R)-N-[2-Fluoro-4-(4-mesylamino- 1.6 (s, 3H), 3.0 (s, 3H), 7.1 451 Methphenylsulphanyl)phenyl]-2-hydroxy- (m, 2H), 7.2 (d, 2H), 7.4 382-methyl-3,3,3-trifluoropropanamide (d, 2H), 7.6 (m, 2H), 9.6 (s, 1H),10.0 (s, 1H) 349 (R)-N-[2-Fluoro-4-(4-acetylamino- 1.6 (s, 3H), 2.1 (s,3H), 7.0 415 Meth phenylsulphanyl)phenyl]-2-hydroxy- (m, 2H), 7.4 (d,2H), 7.6 38 2-methyl-3,3,3-trifluoropropanamide (m, 4H), 10.1 (s, 1H)

EXAMPLES 350-352

[0794] Following the procedure of Method 10 and using the appropriatestarting material the following compounds were prepared. Ex Compound NMRMS SM 350 (R)-N-[2-Fluoro-4-(4-amino- 1.6 (s, 3H), 6.2 (s, 2H), 6.6 (d,405 Meth 65 phenylsulphonyl)phenyl]-2- 2H), 7.5 (d, 2H), 7.7 (q, 3H),7.9 hydroxy-2-methyl-3,3,3- (9t, 1H), 9.8 (s, 1H) trifluoropropanamide351 (R)-N-[2-Chloro-4-(2- 1.6 (s, 3H), 6.2 (s, 2H), 6.6 (t, 421 Meth 67aminophenylsulphonyl) 1H), 6.8 (d, 1H), 7.3 (t, 1H), 7.7phenyl]-2-hydroxy-2-methyl- (d, 1H), 7.9 (m, 2H), 8.1 (s, 1H),3,3,3-trifluoropropanamide 8.2 (d, 1H), 9.9 (s, 1H) 352(R)-N-[2-Chloro-4-(3- 1.59 (s, 3H), 5.65 (s, 2H), 6.78 421 Meth 68aminophenylsulphonyl) (d, 1H), 7.01 (d, 1H), 7.07 (s,phenyl]-2-hydroxy-2-methyl- 1H), 7.2 (t, 1H), 7.88 (d, 1H),3,3,3-trifluoropropanamide 7.98 (s, 1H), 8.27 (d, 1H)

EXAMPLE 353

[0795](R)-N-[2-Chloro-4-(4-dimethylaminoacetylaminophenylsulphanyl)phenyl]-2-hydroxy-2methyl-3,3,3-trifluoropropanamide

[0796] Dimethylamine (0.17 ml of a 40% solution in water) was added to asolution of(R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methyl-3 3,3-trifluoropropanamide (Method 19) (0.25 g) inacetone (1.5 ml). After 24 hours volatile material was removed byevaporation and the residue was dissolved in ethyl acetate, washed withwater, and the organic layer was poured onto a Varian Chem Elut column.Elution with ethyl acetate gave the title compound (0.25 g) as a foam.NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H),7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H) 9.9 (s, 1H); MS(ESP⁻): 474.

EXAMPLE 354

[0797](R)-N-{2-Chloro4-[4-(3-ethylureido)phenylsulphonyl[phenyl}-2-hydroxy-2-methyl-33,3trifluoropropanamide

[0798](R)-2,3,4,5-H₄-3-{2-Chloro4-[4-(3-ethylureido)phenylsulphanyl]phenyl}-2,4-dioxo-5-methyl-5-trifluoromethyloxazole (Method 42) was oxidisedby the procedure of Method 63 then hydrolysed by the method of Example171 to give the title compound. NMR: 1.0 (s, 3H), 1.6 (s, 3H), 3.1 (s,2H), 6.2 (s, 1H), 7.6 (d, 2H), 7.9 (m, 5H), 8.2 (d, 1H), 9.0 (s, 1H),9.8 (s, 1H); MS (ESP⁻): 492.

EXAMPLE 355

[0799] By the procedure of Example 354 using the appropriate startingmaterials the following compound was prepared. Ex Compound NMR MS SM 355(R)-N-[2-Chloro-4-(4- (CDCl₃) 1.8 (s, 3H), 3.8 (s, 1H), 421 Meth 40aminophenylsulphonyl) 4.2 (s, 2H), 6.6 (d, 3H), 7.7 (d,phenyl]-2-hydroxy-2-methyl- 2H), 7.8 (d, 1H), 7.9 (s, 1H),3,3,3-trifluoropropanamide 8.6 (d, 1H), 9.3 (s, 1H)

EXAMPLES 356-380

[0800] The aniline starting material was acylated with an appropriateacid chloride by the procedure of Method 17 or sulphonylated with anappropriate sulphonyl chloride by the procedure of Method 26. There werethus obtained the following compounds. Ex Compound NMR or HPLC MS SM 356(R)-N-[2-Chloro-4-(4-methyl- 1.55 (s, 3H), 2.33 (s, 3H), 7.08 (d, 435 Exphenylsulphonamido)phenyl]- 1H), 7.18 (s, 1H), 7.38 (m, 2H), 2082-hydroxy-2-methyl-3,3,3- 7.68 (m, 4H), 9.54 (s, 1H), 10.43trifluoropropanamide (brs, 1H) 357 (R)-N-[2-Chloro-4-(phenyl- (CDCl₃)1.72 (s, 3H), 3.55 (s, 1H), 423 Ex sulphonamido)phenyl]-2- 6.52 (s, 1H),6.92 (d, 1H), 7.30 (s, (M + H)⁺ 208 hydroxy-2-methyl-3,3,3- 1H), 7.50(t, 2H), 7.59 (m, 1H), trifluoropropanamide 7.78 (d, 2H), 8.24 (d, 1H),8.80 (s, 1H) 358 (R)-N-[2-Chloro-4-(4- 1.55 (s, 3H), 3.80 (s, 3H), 7.09451 Ex methoxyphenylsulphonamido) (m, 3H), 7.19 (s, 1H), 7.65 (s, 208phenyl]-2-hydroxy-2-methyl- 1H), 7.73 (m, 3H), 9.56 (s, 1H)3,3,3-trifluoropropanamide 359 (R)-N-[2-Chloro-4-(4-acetyl- 1.55 (s,3H), 2.06 (s, 3H), 7.08 (d, 478 Ex aminophenylsulphonamido) 1H), 7.19(s, 1H), 7.70 (m, 6H), 208 phenyl]-2-hydroxy-2-methyl- 9.53 (s, 1H),10.27 (s, 1H), 10.36 3,3,3-trifluoropropanamide (brs, 1H) 360(R)-N-[2-Chloro-4-(4-t-butyl- 11.46 minutes (HPLC Method b) 479 Exphenylsulphonamido)phenyl]- (M + H)⁺ 208 2-hydroxy-2-methyl-3,3,3-trifluoropropanamide 361 (R)-N-[2-Chloro-4-(3,4-di-  8.02 minutes (HPLCMethod a) 483 Ex methoxyphenylsulphonamido) (M + H)⁺ 208phenyl]-2-hydroxy-2-methyl- 3,3,3-trifluoropropanamide 362(R)-N-[2-Chloro-4-(4-fluoro-  8.28 minutes (HPLC Method a) 439 Exphenylsulphonamido)phenyl]- 208 2-hydroxy-2-methyl-3,3,3-trifluoropropanamide 363 (R)-N-[2-Chloro-4-(2-chloro-  8.34 minutes(HPLC Method a) 455 Ex phenylsulphonamido)phenyl]- 2082-hydroxy-2-methyl-3,3,3- trifluoropropanamide 364(R)-N-[2-Chloro-4-(2-methyl-  8.35 minutes (HPLC Method a) 435 Exphenylsulphonamido)phenyl]- 208 2-hydroxy-2-methyl-3,3,3-trifluoropropanamide 365 (R)-N-[2-Chloro-4-(4-  8.27 minutes (HPLCMethod a) 415 Ex methoxybenzoylamino)phenyl]- 2082-hydroxy-2-methyl-3,3,3- trifluoropropanamide 366(R)-N-[2-Chloro-4-(t-butyl-  8.3 minutes (HPLC Method a) 365 Excarboxamido)phenyl]-2- 208 hydroxy-2-methyl-3,3,3- trifluoropropanamide367 (R)-N-(2-Chloro-4-acetamido-  7.21 minutes (HPLC Method a) 323 Exphenyl)-2-hydroxy-2-methyl- 208 3,3,3-trifluoropropanamide 368(R)-N-[2-Chloro-4-(benzyl-  8.28 minutes (HPLC Method a) 399 Excarboxamido)phenyl]-2- 208 hydroxy-2-methyl-3,3,3- trifluoropropanamide369 (R)-N-[2-Chloro-4-(2-chloro-  7.76 minutes (HPLC Method a) 421 Expyrid-3-ylcarboxamido) 208 phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide 370¹ (R)-N-[2-Chloro-4-(isoxazol-5-  9.41minutes (HPLC Method b) 376 Ex ylcarboxamido)phenyl]-2- 208hydroxy-2-methyl-3,3,3- trifluoropropanamide 371(R)-N-[2-Chloro-4-(N′-(3- 1.62 (m, 1H), 1.96 (s, 3H), 2.50 587 Exmethylsulphanylpropyl)-2- (m, 2H), 3.41 (s, 3H), 3.88 (t, 2H), 390mesylphenylsulphonamido) 7.29 (dd, 1H), 7.47 (s, 1H), 7.80-phenyl]-2-hydroxy-2-methyl- 8.03 (m, 5H), 8.27 (d, 1H), 9.733,3,3-trifluoropropanamide (s, 1H) 372 (R)-N-[2-Chloro-4-(N′-(3- 1.58(m, 5H), 1.95 (s, 3H), 2.45 509 Ex methylsulphanylpropyl)phenyl- (m,2H), 3.61 (t, 2H), 7.10 (dd, 390 sulphonamido)phenyl]-2- 1H), 7.28 (s,1H), 7.63 (m, 4H), hydroxy-2-methyl-3,3,3- 7.75 (m, 1H), 7.90 (brs, 1H),8.00 trifluoropropanamide (d, 1H), 9.73 (brs, 1H). 373(R)-N-{2-Chloro-4-[N′-(3- 1.60 (m, 5H), 1.95 (s, 3H), 2.46 523 Exmethylsulphanylpropyl)-4- (m, 5H), 3.60 (t, 2H), 7.08 (dd, 390methylphenylsulphonamido] 1H), 7.30 (s, 1H), 7.43 (q, 4H),phenyl}-2-hydroxy-2-methyl- 7.80 (brs, 1H), 7.97 (d, 1H), 9.713,3,3-trifluoropropanamide (brs, 1H) 374 (R)-N-[2-Methyl-4-(phenyl-(CDCl₃) 1.71 (s, 3H), 2.21 (s, 3H), 402 Ex sulphonamido)phenyl]-2- 3.62(s, 1H), 6.41 (brs, 1H), 6.83 209 hydroxy-2-methyl-3,3,3- (dd, 1H), 6.98(m, 1H), 7.40-7.48 trifluoropropanamide (m, 2H), 7.50-7.60 (m, 1H),7.65- 7.70 (s, 1H), 7.71-7.7 9m, 1H), 8.00 (brs, 1H). 375(R)-N-[2-Methyl-4-(2-phenyl- (CDCl₃) 1.6 (s, 3H), 2.22 (s, 3H), 427 ExE-ethenylsulphonamido) 3.75 (brs, 1H), 6.48 (brs, 1H), 209phenyl]-2-hydroxy-2-methyl- 6.75 (d, 1H), 6.99-7.06 (m, 1H),3,3,3-tnfluoropropanamide 7.07-7.10 (m, 1H), 7.30-7.42 (m, 5H), 7.55 (d,1H), 7.69-7.73 (m, 1H), 8.06 (brs, 1H). 376 (R)-N-[2-Methyl-4-(4-methyl-(CDCl₃) 1.66 (s, 3H), 2.17 (s, 3H), 415 Ex phenylsulphonamido)phenyl]-2.38 (s, 3H), 3.70 (brs, 1H), 6.53 209 2-hydroxy-2-methyl-3,3,3- (brs,1H), 6.80-6.85 (m, 1H), trifluoropropanamide 6.95-6.98 (m, 1H),7.20-7.28 (m, 1H), 7.61-7.69 (m, 3H), 8.05 (brs, 1H). 377(R)-N-[2-Methyl-4-(2-mesyl- (CDCl₃) 1.68 (s, 3H), 2.15 (s, 3H), 479 Exphenylsulphonamido)phenyl]- 3.48 (s, 3H), 3.65 (s, 1H), 6.97- 2092-hydroxy-2-methyl-3,3,3- 7.04 (m, 2H), 7.59-7.88 (m, 3H),trifluoropropanamide 7.94-8.11 (m, 2H), 8.11 (brs, 1H), 8.30-8.33 (m,1H). 378 (R)-N-[2-Methyl-4-(2- (CDCl₃) 1.50 (s, 3H), 2.18 (s, 3H), 469Ex trifluoromethylphenyl- 3.60 (s, 1H), 6.61 (brs, 1H), 6.87- 209sulphonamido)phenyl]-2- 6.92 (m, 1H), 6.98-7.02 (m, 1H),hydroxy-2-methyl-3,3,3- 7.50-7.75 (m, 3H), 7.84-7.92 (m,trifluoropropanamide 1H), 7.97-8.10 (m, 2H). 379(R)-N-(2-Methyl-4-mesyl- (CDCl₃) 1.75 (s, 3H), 2.27 (s, 3H), 339 Examinophenyl)-2-hydroxy-2- 3.00 (s, 3H), 3.62 (brs, 1H), 6.28 209methyl-3,3,3- (brs, 1H), 7.08-7.14 (m, 1H), trifluoropropanamide7.11-7.14 (m, 1H), 7.77-7.82 (m, 1H), 8.06 (brs, 1H). 380(R)-N-[2-Methyl-4-(2-chloro- (CDCl₃) 1.72 (s, 3H), 2.22 (s, 3H), 351 Exphenylsulphonamido)phenyl]- 3.67 (s, 1H), 5.91-5.98 (m, 1H), 2092-hydroxy-2-methyl-3,3,3- 6.21-6.29 (m, 1H), 6.38 (brs, 1H),trifluoropropanamide 6.48-6.58 (m, 1H), 6.93-7.00 (m, 1H), 7.01-7.05 (m,1H), 7.70-7.78 (m, 1H), 8.05 (brs, 1H).

EXAMPLE 381

[0801](R)-N-[2-Chloro-4-(3-phenylureido)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0802] A mixture of(R)-N-[2-chloro-4-aminophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 208) (0.198 g) and phenyl isocyanate (0.09 ml) in diethyl ether(10 ml) was stirred for 22 hours then evaporated to dryness. The residuewas partitioned between water (25 ml) and ethyl acetate (50 ml). Theorganic phase was washed with brine (25 ml), dried and concentrated byevaporation to give the title compound (170 mg) as a foam.

[0803] NMR: 1.66 (s, 3H), 7.04 (t, 1H), 7.35 (m, 3H), 7.52 (d, 1H), 7.71(s, 1H), 7.86 (m, 2H), 8.77 (s, 1H), 8.92 (s, 1H), 9.63 (s, 1H); MS(ESP⁻): 400.

EXAMPLE 382

[0804](R)-N-{2-Chloro-4-[N-(4-methylphenylsulphonyl)(N-methyl)amino]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0805] A mixture of(R)-N-[2-chloro4-(4-methylphenylsulphonamido)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 356) (0.137 g), anhydrous potassium carbonate (0.043 g) andiodomethane (0.038 ml) in acetone (8 ml) was stirred for 64 hours.Volatile material was removed by evaporation and the residue wasdissolved in ethyl acetate, washed with water and brine then dried.Volatile material was removed by evaporation and the residue waspurified by elution through a Varian Isolute silica 10 g column with 30%ethyl acetate/hexane as eluent to give the title compound (0.079 g).NMR: 1.60 (s, 3H), 2.38 (s, 3H), 3.11 (s,3H), 7.11 (d, 3H), 7.32 (s,1H), 7.43 (m, 4H), 7.94 (d, 1H), 9.67 (brs, 1H); MS (ESP⁻): 449.

EXAMPLES 383-387

[0806] By the method of Example 382 and using the appropriate startingmaterials the following compounds were prepared. Ex Compound HPLC MS SM383 (R)-N-{2-Chloro-4-[N-(4-t-butylphenylsulphonyl) 12.36 minutes 493 Ex(N-methyl)amino]phenyl}-2-hydroxy-2-methyl- (HPLC Method (M + H)⁺ 3603,3,3-trifluoropropanamide b) 384(R)-N-{2-Chloro-4-[N-(3,4-dimethoxypheny l-  10.7 minutes 497 Exsulphonyl)(N-methyl)amino]phenyl}-2-hydroxy- (HPLC Method (M + H)⁺ 3612-methyl-3,3,3-trifluoropropanamide b) 385(R)-N-{2-Chloro-4-[N-(4-fluorophenylsulphonyl) 11.14 minutes 455 Ex(N-methyl)amino]phenyl}-2-hydroxy-2-methyl- (HPLC Method (M + H)⁺ 3623,3,3-trifluoropropanamide b) 386(R)-N-{2-Chloro-4-[N-(2-chlorophenylsulphonyl) 11.24 minutes 471 Ex(N-methyl)amino]phenyl}-2-hydroxy-2-methyl- (HPLC Method (M + H)⁺ 3633,3,3-trifluoropropanamide b) 387(R)-N-{2-Chloro-4-[N-(2-methylphenylsulphonyl)  11.3 minutes 449 Ex(N-methyl)amino]phenyl}-2-hydroxy-2-methyl- (HPLC Method 3643,3,3-trifluoropropanamide b)

EXAMPLES 388-389

[0807] Following the procedure of Method 30 (see below) and using theappropriate starting materials the following compounds were prepared. ExCompound NMR MS SM 388 (R)-N-[2-Chloro-4-(2- 1.56 (s, 3H), 4.76 (s, 2H),6.56 (t, 372 Ex 206 aminoanilino)phenyl]-2- 1H), 6.66 (m, 2H), 6.75 (d,1H), hydroxy-2-methyl-3,3,3- 6.89 (t, 1H), 6.97 (d, 1H), 7.40 (s,trifluoropropanamide 1H), 7.52 (m, 2H), 9.39 (s, 1H) 389(R)-N-(2-Methoxy-4-amino- (CDCl₃) 1.51 (s, 3H), 3.74 (s, 3H), 277 Meth61 phenyl)-2-hydroxy-2- 5.00 (brs, 2H), 6.05-6.15 (m, 1H), methyl-3,3,3-6.28-6.37 (m, 1H), 7.53 (brs, 1H), trifluoropropanamide 7.72-7.78 (m,1H), 9.08 (brs, 1H)

EXAMPLE 390

[0808](R)-N-[2-Chloro-4-(3-methylsulphanylpropylamino)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0809] Sodium triacetoxyborohydride (0.297 g) was added to a solution of3-methylsulphanylpropionaldehyde (0.1 ml) and(R)-N-(2-chloro-4-aminophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 208) (0.282 g) in 1,2-dichloroethane (6 ml). The mixture wasstirred for 16 hours. Saturated aqueous sodium hydrogen carbonate (25ml) was added and the mixture was extracted with ethyl acetate (40 ml).The extracts were washed with brine (15 ml) then dried. Volatilematerial was removed by evaporation and the residue was purified bychromatography on a Varian Isolute silica column eluting with 25% ethylacetate/hexane. The resulting solid was triturated with ether to givethe title compound (0.089 g) as a solid. NMR: 1.54 (s, 3H), 1.78 (m,2H), 2.05 (s, 3H), 2.55 (q, 2H), 3.09 (q, 2H), 5.93 (t, 1H), 6.54 (dd,1H), 6.65 (s, 1H), 7.46 (m, 2H), 9.33 (s, 1H); MS (ESP⁻): 369.

EXAMPLES 391-393

[0810] By the method of Example 390 and using the appropriate startingmaterials and Example 208 the following compounds were prepared. ExCompound NMR MS 391 (R)-N-[2-Chloro-4-(benzyl- 1.54(s, 3H), 4.26(d, 2H),6.53(m, 2H), 371 amino)phenyl]-2-hydroxy-2- 6.65(s, 1H), 7.20(m, 1H),7.30(m, 4H), methyl-3,3,3-trifluoropropanamide 7.40(d, 1H), 7.45(s, 1H),9.30(s, 1H) 392 (R)-N-[2-Chloro-4-(1- 1.56(s, 3H), 3.55(s, 3H), 4.15(d,2H), 374 methylpyrrol-2-ylmethyl 5.88(m, 1H), 5.97(m, 1H), 6.13(t, 1H),amino)phenyl]-2-hydroxy-2- 6.65(m, 2H), 6.77(s, 1H), 7.46(d, 2H),methyl-3,3,3-trifluoropropanamide 9.37(brs, 1H)  393¹(R)-N-[2-Chloro-4-(pyridin-4- 1.54(s, 3H), 4.34(d, 2H), 6.53(dd, 1H),372 ylmethylamino)phenyl]-2-hydroxy- 6.65(s, 1H), 6.69(t, 1H), 7.33(d,2H), 2-methyl-3,3,3- 7.41(d, 1H), 7.53(brs, 1H), 8.48(d,trifluoropropanamide 2H), 9.37(s, 1H)

EXAMPLE 394

[0811] (R)-N-[2-Chloro-4-(phenylsulphonyl)phenyl]-2-aminopropanamide

[0812] TFA (0.5 ml) was added drop wise to a solution of(R)-N-[2-chloro4-(phenylsulphonyl)phenyl]-2-(t-butoxycarbonylamino)propanamide(Method 2) (0.090 g) in dry DCM (5 ml). The resulting mixture wasstirred at room temperature for 3 hours. Volatile material was removedby evaporation. The resulting residue was re-dissolved in DCM (10 ml),and volatile material was removed by evaporation. This was repeated, theresulting residue was dried for 30 minutes on a high vacuum line. Theresidue was then dissolved in DCM and passed through a Varian IsoluteSPE column containing basic residues, with DCM as the eluent to give thetitle compound (0.067 g) as a gum. NMR (CDCl₃): 1.32-1.40 (d, 3H), 1.52(brs, 2H), 3.51-3.64 (q, 1H), 7.40-7.55 (m, 3H), 7.71-7.80 (m, 1H),7.81-7.95 (m, 3H) 8.58-8.65 (m, 1H), 10.46 (brs, 1H). MS: (ESP⁺) 339.3(M+H)⁺.

EXAMPLES 395-396

[0813] By the method of Example 394 and using the appropriate startingmaterials the following compounds were prepared. Ex Compound NMR MS SM395 (R)-N-{2-Chloro-4-[4- 1.65(s, 3H), 2.65(brs, 2H), 2.8 518 Ex 220(piperazin-1-ylcarbonyl) (brs, 2H), 3.2(brs, 2H), 3.6(brs,phenylsulphonyl]phenyl}-2- 2H), 7.65(d, 2H), 8.0-8.15(m, 4H),hydroxy-2-methyl-3,3,3- 8.2(s, 1H), 8.4(d, 2H), 9.6(s, 1H)trifluoropropanamide 396 (R)-N-{2-Chloro-4-(3-amino- 1.56(s, 3H),1.61-1.66(m, 2H), 387 Ex 51  propylsulphonyl)phenyl}-2- 2.62(t, 2H),3.34-3.39(t, 2H), hydroxy-2-methyl-3,3,3- 7.78-7.82(m, 1H), 7.94(s, 1H),trifluoropropanamide 8.35(d, 1H)

EXAMPLE 397

[0814](R)-N-[2-Chloro-4-(4-{3-hydroxypropoxy}phenylsulphinyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0815] Sodium hydride (0.06 g of a 60% dispersion in oil) was added to asolution of(R)-N-[2-chloro-4-(4-hydroxyphenylsulphinyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 89) (0.5 g) in DMF (5 ml) at 0° C. The mixture was stirred for15 minutes then 3-bromopropanol (0.12 ml) was added as a solution in DMF(3 ml). The mixture was stirred at ambient temperature for 16 hours.Volatile material was removed by evaporation and the residue waspurified by chromatography on a silica gel Mega Bond Elut column elutingwith 0-10% methanol/DCM to give the title compound (0.34 g) as a gum.

[0816] NMR (CDCl₃): 1.25 (dd, 2H), 1.7 (s, 3H), 1.8 (s, 1H), 3.8-3.9 (m,2H), 4.1-4.2 (m, 2H), 5.1 (s, 1H), 6.95 (d, 2H), 7.4 (d, 1H), 7.5 (d,2H), 7.6-7.65 (m, 1H), 8.45-8.55 (m, 1H), 9.3 (s, 1H);

[0817] MS (ESP⁻): 464.

EXAMPLES 398-400

[0818] By the procedure of Example 397 and using Example 89 as thestarting materials the following compounds were prepared. Ex CompoundNMR MS  398¹ (R)-N-[2-Chloro-4-(4-{3-amino- 1.6(s, 3H), 1.95-2.0(m, 2H),2.90-3.0 465 propoxy}phenylsulphinyl)phenyl]- (m, 2H), 4.0-4.1(m, 2H),7.1(m, 2H), (M + H)⁺ 2-hydroxy-2-methyl-3,3,3- 7.6-7.7(m, 3H),7.7-7.9(m, 4H), 8.1 trifluoropropanamide (d, 1H), 9.85(s, 1H) 399(R)-N-[2-Chloro-4-(4-{carbamoyl- 1.6(s, 3H), 4.45(d, 2H), 6.9-7.0(m, 463methoxy}phenylsulphinyl)phenyl]- 1H), 7.0-7.2(m, 2H), 7.3-7.5(m, 2H),2-hydroxy-2-methyl-3,3,3- 7.5-7.6(m, 1H), 7.6-7.7(m, 2H), 7.8trifluoropropanamide (s, 1H), 8.1(d, 1H), 9.8(s, 1H) 400(R)-N-[2-Chloro-4-(4-{N,N- 1.6(s, 3H), 2.8(s, 3H), 3.0(s, 3H), 491dimethylcarbamoylmethoxy}pheny 4.8-5.0(m, 2H), 6.8(d, 1H), 7.0-7.1lsulphinyl)phenyl]-2-hydroxy-2- (m, 2H), 7.35(d, 1H), 7.5-7.6(d, 2H),methyl-3,3,3-trifluoropropanamide 7.8(d, 1H), 8.15(d, 1H), 9.8(s, 1H)

EXAMPLE 401

[0819] By the procedure of Method 26 (see below) and using Example 396as the starting materials the following compound was prepared. ExCompound NMR MS 401 (R)-N-{2-Chloro-4-(3- 1.61(s, 3H), 1.67-1.77(m, 465mesylaminopropylsulphonyl) 2H), 2.84(s, 3H), 2.96-phenyl}-2-hydroxy-2-methyl- 3.02(m, 2H), 3.36-3.42(m,3,3,3-trifluoropropanamide 2H), 7.02(t, 1H), 7.86- 7.9(m, 1H), 8.02(s,1H), 8.34(d, 1H), 9.92(s, 1H)

EXAMPLE 402

[0820](R)-N-[2-Chloro-4-(N,N-dimethylcarbamoylmethylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0821] Tetrabutylammonium fluoride (1.1 ml of a 1M solution in THF) wasadded to(R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Method 28) (0.50 g) in anhydrous THF (5 ml) at -70° C. After 15 minutes2-chlorodimethylacetamide (0.17 ml) was added and the mixture wasallowed to warm up then was stirred at ambient temperature for 45minutes. Ethyl acetate (80 ml) was added and the mixture was washed withbrine (100 ml) then dried and volatile material was removed byevaporation. The residue was purified on a silica gel Mega Bond Elutcolumn eluting with 10-50% ethyl acetate/hexane to give the titlecompound (0.30 g) as a solid. NMR (CDCl₃) 1.72 (s, 3H), 2.97 (s, 3H),3.08 (s, 3H), 3.71 (s, 2H), 4.76 (s, 1H), 7.32-7.36 (m, 1H), 7.53 (d,1H), 8.32 (d, 1H), 9.05 (s, 1H); MS (ESP⁻): 383.

EXAMPLES 403-412

[0822] Following the procedure of Example 402 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR MS SM  403 (R)-N-[2-Chloro-4- (CDCl₃) 1.75(s, 3H), 3.55(s, 3H), 370Meth 28 (methoxycarbonylmethyl 3.72(s, 2H), 7.33-7.37(m, 1H),sulphanyl)phenyl]-2- 7.49(s, 1H), 8.32(d, 1H), 8.85(s,hydroxy-2-methyl-3,3,3- 1H) trifluoropropanamide  404(R)-N-[2-Chloro-4-({3- (CDCl₃) 1.76(s, 3H), 1.78-1.83 383 Meth 28N,N-dimethylamino- (m, 2H), 2.24(s, 6H), 2.43(t, 2H),propyl}sulphanyl)phenyl]- 2.93(t, 2H), 7.24(d, 1H), 7.36(s,2-hydroxy-2-methyl-3,3,3- 1H), 8.30(d, 1H), 9.25(s, 1H)trifluoropropanamide   405¹ (R)-N-[2-Chloro-4-(3-t- (CDCl₃): 1.44(s,9H), 1.76(s, 3H), 455 Meth 28 butoxycarbonylamino- 1.81(t, 2H), 2.92(t,2H), 3.20- and Meth propylsulphanyl)phenyl]- 3.26(m, 2H), 3.97(s, 1H),4.60(s, 20 2-hydroxy-2-methyl-3,3,3- 1H), 7.23-7.28(m, 1H), 7.36(s,trifluoropropanamide 1H), 8.28(d, 1H), 8.86(s, 1H)   406¹(R)-N-{2-Chloro-4-(3- (CDCl₃): 1.75(s, 3H), 1.83(t, 2H), 397 Meth 28acetamidopropyl- 2.05(s, 3H), 2.91(t, 2H), 3.33-3.4 and Methsulphanyl)phenyl}-2- (m, 2H), 5.63(brs, 1H), 7.25-7.27 21hydroxy-2-methyl-3,3,3- (m, 1H), 7.36(s, 1H), 8.3(d, 1H),trifluoropropanamide 9.06(s, 1H)   407¹ (R)-N-{2-Chloro-4-(2- (CDCl₃)1.76(s, 3H), 3.52-3.60 338 Meth 28 propenylsulphanyl)phenyl}- (m, 2H),5.07-5.15(m, 2H), 5.78- and allyl 2-hydroxy-2-methyl- 6.10(m, 1H),7.27-7.28(m, 1H), bromide 3,3,3-trifluoropropanamide 7.40(s, 1H),8.27(d, 1H), 8.78(s, 1H)   408² (R)-N-{2-Chloro-4-(2- (CDCl₃) 0.97(t,3H), 1.47-(CDCl₃) 370 Meth 28 hydroxybutylsulphanyl) 1.62(m, 3H),1.74(s, 3H), 2.25(d, phenyl}-2-hydroxy-2- 1H), 2.28-2.29(m, 1H),3.09-3.14 methyl-3,3,3- (m, 1H), 7.29-7.34(m, 1H), 7.44trifluoropropanamide (s, 1H), 7.44(s, 1H), 8.30(d, 1H), 8.86(s, 1H)  409³ (R)-N-{2-Chloro-4-(2- (CDCl₃) 1.31(s, 6H), 1.71(s, 3H), 370 Meth28 hydroxy-2-methylpropyl- 3.09(s, 2H), 7.32-7.36(m, 1H),sulphanyl)phenyl}-2- 7.46(s, 1H), 8.23(d, 1H), 8.81(s,hydroxy-2-methyl-3,3,3- 1H) trifluoropropanamide    410^(1,4)(R)-N-{2-Chloro-4- (CDCl₃) 1.02(t, 3H), 1.62-1.69 340 Meth 28propylsulphanylphenyl}-2- (m, 2H), 1.75(s, 3H), 2.87(t, 2H),hydroxy-2-methyl-3,3,3- 3.66(s, 1H), 7.24-7.27(m, 1H),trifluoropropanamide 7.36(s, 1H), 8.25(d, 1H), 8.77(s, 1H)    411^(1,4)(R)-N-{2-Chloro-4-(n- (CDCl₃) 0.92(t, 3H), 1.38-1.50 354 Meth 28butylsulphanyl)phenyl}-2- (m, 2H), 1.59-1.66(m, 2H), 1.74hydroxy-2-methyl-3,3,3- (s, 3H), 2.89(t, 2H), 3.65(s, 1H),trifluoropropanamide 7.23-7.26(m, 1H), 7.36(s, 1H), 8.25(d, 1H), 8.76(s,1H)   412⁵ (R)-N-[2-Ethynyl-4-(4- (CDCl₃ + 1 drop DMSO-δ₆) 1.84(s, 474Meth 57 mesylphenylsulphonyl) 3H), 3.05(s, 3H), 3.64(s, 1H),phenyl]-2-hydroxy-2- 6.60(s, 1H), 7.92(m, 1H), 8.05(d, methyl-3,3,3-1H), 8.09-8.13(m, 4H), 8.68(d, trifluoropropanamide 1H), 9.91(s, 1H)

EXAMPLE 413

[0823]N-[2-Fluoro4-(4-methylsulphanylphenylsulphanyl)phenyl]-2-hydroxy-2-trifluoromethyl-3,3,3-trifluoropropanamide

[0824] Tetra-n-butylammonium fluoride (0.48 ml of a 1M solution in THF)was added to a stirred solution ofN-[2-fluoro-4-(4-methylsulphanylphenylsulphanyl)phenyl]-2-(t-butyldimethylsilyloxy)-2-trifluoromethyl-3,3,3-trifluoropropanamide(0.278 g) (Method 55) in anhydrous THF (5 ml) at −78° C. under argon.After 30 minutes ethyl acetate (50 ml) was added and the mixture waswashed with aqueous hydrochloric acid (2M, 30 ml) and brine (30 ml) thendried. Volatile material was removed by evaporation and the residue waspurified on a silica gel Mega Bond Elut column eluting with 10-30% ethylacetate/iso-hexane to give the title compound (0.199 g) as a pale yellowsolid. NMR (CDCl₃): 2.50 (s, 3H), 5.12 (s, 1H), 6.98 (d, 1H), 7.05 (d,1H), 7.23 (d, 2H), 7.35 (d, 2H), 8.05-8.08 (m, 1H); MS (ESP⁻): 458,

EXAMPLE 414

[0825](R)-N-{2-Chloro-4-(2-propenylsulphonyl)phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0826] A solution of Oxone (1.44 g) in water (15 ml) was added to asolution of(R)-N-{2-chloro-4-(2-propenylsulphanyl)phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 407) (0.389 g) in methanol (15 ml). The mixture was stirred for1.5 hours. Water (50 ml) was added and the mixture extracted into ethylacetate (100 ml) and dried. Volatile material was removed by evaporationand the residue purified on a silica gel Mega Bond Elut column elutingwith 20-30% ethyl acetate/iso-hexane to give the title compound as afoam (0.180 g). NMR: 1.61 (s, 3H), 4.18 (d, 2H), 5.18-5.32 (m, 2H),5.61-5.75 (m, 1H), 7.82-7.85 (m, 1H), 7.98 (s, 1H), 8.01 (s, 1H), 8.33(d, 1H), 9.91 (s, 1H); MS (ESP⁻): 370.

EXAMPLE 415

[0827](R)-N-[2-Chloro-4-(2-hydroxyethylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0828] A solution of(R)-N-[2-chloro-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (0.8 g) in pyridine (1 ml) was added to a deoxygenatedsolution of 2-mercaptoethanol (0.18 ml), sodium methoxide (0.14 g) andcopper (I) chloride (0.2 g) in quinoline (2 ml) and pyridine (2 ml). Themixture was heated to 190° C. under argon for 18 hours. The mixture wasallowed to cool to room temperature then dissolved in ethyl acetate (100ml), washed with dilute aqueous hydrochloric acid (2×50 ml) and brine(2×50 ml) then dried. Volatile material was removed by evaporation andthe residue was purified by chromatography on a silica gel Mega BondElut column eluting with 10-60% ethyl acetate/iso-hexane to give thetitle compound as a gum. NMR (CDCl₃): 1.76 (s, 3H), 3.10 (t, 2H),3.75-80 (m, 2H), 7.31-7.34 (m, 1H), 7.47 (s, 1H), 8.31 (d, 1H), 8.86 (s,1H); MS (ESP⁻): 342.

EXAMPLES 416-427

[0829] Following the procedure of Example 415 and using the appropriatestarting materials the following compounds were prepared. Ex CompoundNMR (CDCl₃) MS 416 (R)-N-[2-Chloro-4-(cyclopropyl- 0.10-0.13(m, 1H),0.5-0.55(m, 1H), 352 methylsulphanyl)phenyl]-2- 0.81-0.89(m, 1H),1.76(s, 3H), 2.84 hydroxy-2-methyl-3,3,3- (d, 2H), 7.26-7.30(m, 1H),7.42(s, trifluoropropanamide 1H), 8.26(d, 1H), 8.78,(s, 1H) 417(R)-N-[2-Chloro-4-(cyclohexyl- 1.23-1.31(m, 6H), 1.57(s, 3H), 1.73- 380sulphanyl)phenyl]-2-hydroxy-2- 1.76(m, 4H), 3.02-3.10(m, 1H),methyl-3,3,3-trifluoropropanamide 7.31-7.34(m, 1H), 7.44(s, 1H), 8.28(d, 1H), 8.81(s, 1H) 418 (R)-N-[2-Chloro-4-(thien-2- 1.77(s, 3H),3.66(s, 1H), 4.27(s, 394 ylmethylsulphanyl)phenyl]-2- 2H), 6.83-6.90(m,2H), 7.16-7.19(d, hydroxy-2-methyl-3,3,3- 1H), 7.17(d, 1H), 7.38(s, 1H),8.28 trifluoropropanamide (d, 1H), 8.86(brs, 1H) 419(R)-N-[2-Chloro-4-(N,N-dimethyl- 1.73(s, 3H), 2.26(s, 6H), 2.55(t, 369aminoethylsulphanyl)phenyl]-2- 2H), 3.02(t, 2H), 7.26-7.28(m, 1H)hydroxy-2-methyl-3,3,3- 7.40(s, 1H), 8.31(d, 1H), 8.07(s,trifluoropropanamide. 1H) 420 (R)-N-[2-Chloro-4-(N-methyl- 1.73(s, 3H),2.84(d, 3H), 3.6(s, 2H), 369 carbamoylmethylsulphanyl)phenyl]- 6.65(brs,1H), 7.21-7.26(m, 1H), 2-hydroxy-2-methyl-3,3,3- 7.34(s, 1H), 8.34(d,1H), 8.92(s, trifluoropropanamide 1H) 421 (R)-N-[2-Chloro-4-(iso-propyl-1.23-1.30(m, 6H), 1.73(s, 3H), 3.28- 340 sulphanyl)phenyl]-2-hydroxy-2-3.36(m, 1H), 7.31-7.34(m, 1H), 7.44 methyl-3,3,3-trifluoropropanamide(s, 1H), 7.78(d, 1H), 8.84(brs, 1H) 422 (R)-N-[2-Chloro-4-(cyclopentyl-1.52-1.63(m, 7H), 1.71-1.78(m, 4H), 366 sulphanyl)phenyl]-2-hydroxy-2-3.52-3.57(m, 1H), 7.26-7.28(m, 1H), methyl-3,3,3-trifluoropropanamide7.2(s, 1H), 8.26(d, 1H), 8.78(s, 1H) 423 (R)-N-[2-Chloro-4-(iso-butyl-1.02(s, 6H), 1.73(s, 3H), 1.81-1.89 354 sulphanyl)phenyl]-2-hydroxy-2-(m, 1H), 2.8(d, 2H), 3.67(s, 1H), methyl-3,3,3-trifluoropropanamide7.26-7.31(m, 1H), 7.36(s, 1H), 8.26 (d, 1H), 8.76(s, 1H)  424¹(R)-N-[2-Fluoro-4-ethylsulphanyl- 1.20(t, 3H), 1.65(s, 3H), 2.81-2.89310 phenyl]-2-hydroxy-2-methyl-3,3,3- (q, 2H), 3.60(s, 1H), 7.00-7.05(m,trifluoropropanamide 2H), 8.13(t, 1H), 8.40(brs, 1H) 425(R)-N-[2-Chloro-4-(2,3- 1.71(s, 3H), 3.00-3.05(m, 2H), 3.52- 372dihydroxypropyl)sulphanylphenyl]- 3.60(m, 1H), 3.68-3.78(m, 2H), 6.652-hydroxy-2-methyl-3,3,3- (s, 1H), 7.28-7.31(m, 1H), 7.44(s,trifluoropropanamide 1H), 8.34(d, 1H), 9.42(s, 1H) 426(R)-N-[2-Chloro-4-(2- 1.28(d, 3H), 1.76(s, 3H), 2.81-2.92 356hydroxypropyl)sulphanylphenyl]-2- (m, 1H), 3.02-3.1(m, 1H), 3.65(s,hydroxy-2-methyl-3,3,3- 1H), 3.81-3.89(m, 1H), 7.34(d, 1H),trifluoropropanamide 7.44(s, 1H), 8.31(d, 1H), 8.84(s, 1H) 427(R)-N-[2-Chloro-4-t- 1.28(s, 9H), 1.76(s, 3H), 3.57(s, 354butylsulphanylphenyl]-2-hydroxy-2- 1H), 7.44-7.47(m, 1H), 7.60(s, 1H),methyl-3,3,3-trifluoropropanamide 8.63(d, 1H), 8.92(s, 1H)

EXAMPLE 428

[0830](R)-N-(2-Chloro-4-{(4-acetamidophenyloxy)sulphonyl}phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0831] A solution of(R)-N-{2-chloro-4-[4-chlorosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Method 73) (366 mg, 1.00 mmol) in DCM (25 ml) was added to a stirredsolution of 4-acetamidophenol (151 mg, 1.00 mmol), dimethylaminopyridine(10 mg, 0.08 mmol) and pyridine (0.45 ml, 2.0 mmol) in DCM (25 ml). Theresultant mixture was stirred at ambient temperature overnight,evaporated to dryness and the residue treated with 1M aqueoushydrochloric acid (25 ml). The aqueous solution was extracted with ethylacetate, the ethyl acetate extracts were washed with saturated sodiumhydrogen carbonate solution, brine, dried and evaporated to give, as afoam, the title compound (450 mg, 0.94 mmol); NMR 1.6 (s, 3H), 2.0 (s,3H), 7.00 (d, 2H), 7.55 (d, 2H), 7.8 (dd, 1H), 8.0 (d, 1H), 8.1 (s, 1H),8.4 (d, 1H), 9.9 (s, 1H), 10.03 (s, 1H); MS: m/z 479.

[0832] Preparation of Starting Materials

[0833] The starting materials for the Examples above are eithercommercially available or are readily prepared by standard methods fromknown materials. For example the following reactions are illustrationsbut not limitations of the preparation of some of the starting materialsused in the above reactions.

[0834] Methods 1-2

[0835] Following the procedure of Method 63 (see below) and using theappropriate starting material the following compounds were prepared.Meth Compound NMR SM 1 2-Fluoro-4-phenylsulphonyl- (CDCl₃): 7.5-7.75(m,Meth 8 bromobenzene 6H), 7.91(d, 2H)  2¹ (R)-N-[2-Chloro-4-(phenyl-(CDCl₃): 1.32-1.41(m, Meth 48 sulphonyl)phenyl]-2-(t- 12H), 4.20-4.32(m,1H), butoxycarbonylamino) 4.71-4.80(m, 1H), 7.40- propanamide 7.54(m,3H), 7.70- 7.78(m, 3H), 7.82- 7.92(m, 1H), 8.94(s, br, 1H)

[0836] Methods 3-8

[0837] Following the procedure of Example 187 and using the appropriatestarting materials (SM1 and SM2) the following compounds were prepared.Meth Compound SM 1 SM 2  3¹ 2-Chloro-4- 2-chloro-4- methyl(2-methoxycarbonyl) iodoaniline thiosalicylate phenylsulphanylaniline 42-Chloro-4- 2-chloro-4- methyl (2-ethoxycarbonyl) iodoanilinethiosalicylate phenylsulphanylaniline 5 2-Chloro-4- 2-chloro-4-thiophenol phenylsulphanyl- iodoaniline aniline 6 2-Fluoro-4-2-Fluoro-4- 4-(methyl- (4-(methylsulphanyl) iodoaniline sulphanyl)phenylsulphanyl)aniline thiophenol 7 2-Fluoro-4- 2-Fluoro-4- thiophenolphenylsulphanylaniline iodoaniline  8² 2-Fluoro-4- 2-Fluoro-4-thiophenol phenylsulphanyl-1- iodobromobenzene bromobenzene

[0838] Method 9

[0839] (R)-(+)-2-Hydroxy-2-methyl-3,3,3-trifluoropropanoic acid

[0840] The title compound was resolved according to the resolutionmethod described in European Patent Application No. EP 524781 (describedfor the preparation of the (S)-(−)acid) except that (1S,2R)-norephedrine was used in place of (1R, 2S)-norephedrine or(S)-(−)-1-phenylethylamine. NMR analysis of the acid in the presence of(R)-(+)-1-phenylethylamine gave an enantiomerical purity of >98%; NMR(CDCl₃): 1.27 (s, 3H) for the (R)-enantiomer, 1.21 (s, 3H) for the(S)-enantiomer.

[0841] Method 10

[0842] (4-Acetamidophenylsulphonyl)-2-chloroaniline

[0843] Iron powder (2.5 g) was added to a stirred mixture of4-(4-acetamidophenyl-sulphonyl)-2-chloro-nitrobenzene (Method 13) (0.67g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol(10 ml). The mixture was heated under reflux for 1 hour then evaporatedto near dryness and partitioned between ethyl acetate and water. Theorganic layer was separated, the aqueous layer was extracted with ethylacetate (3×15 ml). The organic extracts were combined and dried.Volatile material was removed by evaporation and the residue waspurified by chromatography on a silica gel Mega Bond Elut column elutingwith 0-2% methanol/DCM to give the title compound (0.18 g) as a solid.NMR: 2.05 (s, 3H), 6.4 (s, 2H), 6.8 (d, 1H), 7.5 (d, 1H), 7.6 (d, 1H),7.8 (q, 4H), 10.3 (brs, 1H); MS (ESP⁻): 323.

[0844] Methods 11-12

[0845] Following the procedure of Method 10 and using the appropriatestarting material the following compounds were prepared. Meth CompoundNMR SM 11 2-Bromo-4-(4-methylsulphanyl- (CDCl₃) 2.44(s, 3H), Methphenylsulphanyl)aniline 4.2(s, 2H), 6.73(d, 1H), 27 7.05-7.22(m, 5H),7.52(d, 1H) 12 (R)-N-[2-Chloro-4-{4-amino- 1.8(s, 3H), 2.2(s, 3H), Methphenylsulphanyl}phenyl]-2- 5.5(s, 2H), 6.6(d, 2H), 18acetoxy-2-methyl-3,3,3- 7.0(m, 3H), 7.2(d, 2H), trifluoropropanamide9.8(s, 1H)

[0846] Method 13

[0847] 4-(4-Acetamidophenylsulphonyl)-2-chloronitrobenzene

[0848] Hydrogen peroxide (0.9 ml of a 30 wt. % solution in water) wasadded to a solution of4-(4-acetamidophenylsulphanyl)-2-chloronitrobenzene (Method 14) (0.78 g)in glacial acetic acid (5 ml) and the mixture was stirred and heated at95° C. for 75 minutes then poured into water (15 ml) and extracted withethyl acetate (3×10 ml). The organic extracts were combined, washed withbrine and then dried. Volatile material was removed by evaporation andthe residue was purified by chromatography on a silica gel Mega BondElut column eluting with 0-50% ethyl acetate/hexane to give the titlecompound (0.68 g). NMR: 2.05 (s, 3H), 7.8 (d, 2H), 7.98 (d, 2H), 8.2-8.3(m, 2H), 8.35-8.45 (m, 1H), 10.4 (brs, 1H); MS (ESP⁻): 353.

[0849] Method 14

[0850] 4-(4-Acetamidophenylsulphanyl)-2-chloronitrobenzene

[0851] A solution of 2-amino-4-(4-acetamidophenylsulphanyl)nitrobenzene(Method 15) (2.4 g) in warm glacial acetic acid (15 ml) was poured ontoice (24 ml). Concentrated hydrochloric acid (4.5 ml) was added and themixture was stirred and cooled to <5° C. A solution of sodium nitrite(0.601 g) in water (5 ml) was added over 7 minutes and the mixture wasstirred for 2 hours at 0-5° C. Aqueous sulphamic acid solution (10% w/v)was added until a negative starch iodide test was observed. In aseparate flask toluene was added to a solution of cuprous chloride(0.852 g) in water (1.2 ml) and concentrated hydrochloric acid (1.3 ml)and the mixture was cooled to <0° C. The first preparation (diazoniumsalt) was then added to the cold cuprous chloride mixture over 5 minutesand the resultant mixture was stirred at ambient temperature for 18hours. The organic layer was separated and the aqueous layer wasextracted with toluene (3×10 ml). The organic extracts were combined,washed with water and brine then dried. Volatile material was removed byevaporation and the residue was purified by chromatography on a silicagel Mega Bond Elut column eluting with 0-15% ethyl acetate/hexane togive the title compound (0.789 g). NMR: 2.1 (s, 3H), 7.1 (dd, 1H), 7.3(d, 1H), 7.5 (d, 2H), 7.7 (d, 2H), 7.95 (d, 1H), 10.2 (brs, 1H).

[0852] Method 15

[0853] 2-Amino4-(4-acetamidophenylsulphanyl)nitrobenzene

[0854] Sodium (0.269 g) was added to ethanol (20 ml) and the resultantsolution was allowed to cool to ambient temperature and4-acetamidothiophenol (1.94 g) was added. The mixture was stirred for 5minutes and 5-chloro-2-nitroaniline (2 g) was added. The mixture wasthen heated under reflux under argon for 3 hours and allowed to cool.The resultant solid was collected by filtration, washed with ethanolthen dried to give the title compound (2.46 g) as a solid. NMR: 2.05 (s,3H), 6.3 (dd, 1H), 6.6 (s, 1H), 7.4 (brs, 2H), 7.5 (d, 2H), 7.7 (d, 2H),7.9 (d, 1H); MS (ESP⁺): 304 (M+H)⁺.

[0855] Method 16

[0856]N-[2-Chloro-4-(4-acetamidophenylsulphonyl)phenyl]-2-acetoxy-2-methylpropanamide

[0857] m-Chloroperoxybenzoic acid (50%, 0.735 g) was added to a solutionofN-[2-chloro-4-(4-acetamidophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide(Method 17) (0.30 g) in DCM (10 ml) and the mixture was stirred atambient temperature for 15 hours. Ethyl acetate (20ml) was added and thesolution was washed with saturated aqueous sodium carbonate solution (10ml) and brine then dried. Volatile material was removed by evaporationand the residue was purified by flash chromatography eluting with 50-80%ethyl acetate/hexane to give the title compound (0.29 g) as a solid. NMR(CDCl₃): 1.7 (s, 6H), 2.2 (2×s, 2×3H), 7.5 (s, 1H), 7.7 (d,2H), 7.8(m,3H), 8.0 (m, 1H), 8.6 (m,2H); MS (ESP⁻): 451; EA: found: C, 52.9; H,4.4; N, 6.1%, C₂₀ H₂₁ClN₂O₆S requires C, 53.0; H, 4.6; N, 6.2%.

[0858] Method 17

[0859]N-[2-Chloro-4-(4-acetamidophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide

[0860]N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide(Method 22) (0.50 g) was dissolved in DCM (10 ml) and cooled to 0-5° C.in an ice bath. Triethylamine (0.46 ml) was added followed by dropwiseaddition of acetyl chloride (0.1 ml) and the mixture was allowed to warmto ambient temperature over 2 hours. Ethyl acetate (20 ml) was added andthe solution was washed with water (2×10 ml) and brine then dried.Volatile material was removed by evaporation and the residue waspurified by flash chromatography eluting with 40-80% ethylacetate/hexane to give the title compound (0.470 g) as a solid. NMR(CDCl₃): 1.8 (s, 6H), 2.2 (d, 6H), 7.2-7.3 (m, 5H), 7.5 (d, 2H), 8.3 (d,1H), 8.4 (s, 1H); MS (ESP⁻): 419; EA: found: C, 56.7; H, 5.0; N, 6.0%;C₂₀H₂₁ClN₂O₄S.0.4 EtOAc requires C, 56.9; H, 5.3; N, 6.1%.

[0861] Methods 18-21

[0862] Following the procedure of Method 17 and using the appropriatestarting material the following compounds were prepared. Meth CompoundNMR SM 18 (R)-N-[2-Chloro-4-{4- 1.8(s, 3H), 2.2(s, 3H), Ex 204nitrophenylsulphanyl} 7.4(t, 3H), 7.6(d, 2H), phenyl]-2-acetoxy-2-7.8(s, 1H), 8.2(d, 2H), methyl-3,3,3- 9.8(s, 1H). trifluoropropanamide19 (R)-N-[2-Chloro-4-{4-(2- 1.8(s, 3H), 2.2(s, 3H), Meth 12chloroacetylamino)- 4.3(s, 2H), 7.1(s, 2H), phenyl sulphanyl}- 7.2(s,1H), 7.4(d, 2H), phenyl]-2-acetoxy-2- 7.7(d, 2H), 9.9(s, 1H),methyl-3,3,3-trifluoro- 10.45(s, 1H) propanamide   20^(1,2)3-(t-Butoxycarbonyl- (CDCl₃): 1.44(s, 9H), 3-amino-amino)-1-bromopropane 2.00-2.09(m, 2H), propyl- 3.33-3.30(m, 2H),bromide.HBr 3.42(t, 2H)  21² 3-Acetamido-1- (CDCl₃): 1.96(s, 3H),3-amino- bromopropane 2.01-2.1(m, 2H), propyl- 3.34-3.46(m, 4H),bromide.HBr 5.65-5.75(brs, 1H)

[0863] Method 22

[0864]N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide

[0865] Copper (I) chloride (0.90 g) was added to a mixture ofN-[2-chloro-4-iodophenyl]-2-acetoxy-3-methylpropanamide (Method 23) (8.3g), 4-aminothiophenol (1.07 ml) and potassium carbonate (9.1 g) in DMF(100 ml). The mixture was heated at 135° C. with stirring under argonfor 3 hours, cooled and then filtered through diatomaceous earth. Thefilter was washed with ethyl acetate (3×20 ml) and the filtrates werecombined and washed with water (50 ml), brine and dried. The volatilematerial was removed by evaporation. The crude product was purified byflash chromatography eluting with 20-40% ethyl acetate/hexane to givethe title compound (4.99 g) as a solid. Mp 130-132° C.; NMR (CDCl₃): 1.7(s, 6H), 2.1 (s, 3H), 3.8 (s, 2H), 6.6 (d, 2H), 7.1 (m, 2H), 7.2 (m,2H), 8.2 (d,1H), 8.4 (s, 1H); MS (ESP⁻): 377.

[0866] Method 23

[0867] AN-[2-Chloro-4-iodophenyl]-2-acetoxy-3-methylpropanamide

[0868] 2-Chloro-4-iodoaniline (5 g) was dissolved in DCM (100 ml) andcooled to 0-5° C. in an ice bath. Pyridine (2.1 ml) was added followedby dropwise addition of 2-acetoxy-2-methylpropanoyl chloride (3.44 ml)and the mixture was allowed to warm to ambient temperature over 15hours. The solvent was removed by evaporation and the residue waspurified by flash chromatography eluting with 10-50% ethylacetate/hexane to give the title compound (7.5 g) as a solid. Mp156-158° C.; NMR (CDCl₃): 1.7 (s, 6H), 2.2 (s, 3H), 7.6 (d, 1H), 7.7 (d,1H), 8.2 (d, 1H), 8.4 (s, 1H); MS (ESP⁻): 380.

[0869] Method 24

[0870] Following the procedure of Method 23 and using the appropriatestarting material the following compound was prepared. Meth Compound NMRSM 24 (R)-N-[2-Chloro- 1.8(s, 3H), 2.2(s, 3H), 7.58(d, 2-Chloro-4-4-nitrophenyl]- 1H), 8.26(d, 1H), 8.41(s, 1H), nitroaniline2-acetoxy-2-methyl- 10.23(s, 1H) and Meth 49 3,3,3-trifluoro-propanamide

[0871] Method 25

[0872] Following the procedure of Methods 23, 22, 17 and 16 and usingthe appropriate starting material the following compound was prepared.Meth Compound 25¹ N-[2-Chloro-4-{4-N-(2,2-dimethylpropanamido)phenylsulphonyl}phenyl]-2- acetoxy-2-methylpropanamide

[0873] Method 26

[0874]N-[2-Chloro-4-{4-(N,N-dimesylamino)phenylsulphanyl}phenyl]-2-acetoxy-2-methylpropanamide

[0875]N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide(Method 22) (0.50 g) was dissolved in DCM (10 m) and cooled to 0-5° C.in an ice bath. Triethylamine (0.55 ml) was added followed by dropwiseaddition of methylsulphonyl chloride (0.11 ml) and the mixture wasallowed to warm to ambient temperature over 2 hours. The solution wasconcentrated then the solid was dissolved in DCM (5 ml) and water (5 ml)was added. The solution was loaded onto a Varian Chem Elut column andafter 3 minutes was washed through with DCM (20 ml). The DCM layer wasthen concentrated and the solid washed with ether and filtered to givethe title compound (0.58 g) as a solid. NMR (CDCl₃): 1.7 (s, 6H), 2.2(s, 3H), 3.4 (s, 6H), 7.2 (s, 4H), 7.4 (d, 1H), 7.5 (d, 1H), 8.4 (d,1H), 8.5 (d 1H); MS (ESP⁻): 533; EA: found: C, 44.4; H, 4.5; N, 5.1%;C₂₀H₂₃ClN₂O₇S₃ requires C, 44.9; H, 4.3; N, 5.2%.

[0876] Method 27

[0877] 2-Bromo-4-(4-methylsulphanylphenylsulphanyl)nitrobenzene

[0878] t-Butyl nitrite (3.1 ml) was added to a slurry of copper (II)bromide (4.4 g) in acetonitrile (85 ml) at 0° C.2-Amino-4-(4-methylsulphanylphenylsulphanyl)nitrobenzene (5.09 g),(prepared by the method described in J. Med. Chem., 1975, 18, 1164 forthe preparation of 2-nitro-5-phenylsulphanylaniline but using4-methylsulphanylthiophenol in place of thiophenol) was addedportionwise over 5 minutes and the mixture was stirred a further 2 hoursat 0° C., allowed to warm to ambient temperature, and stirred a further16 hours. Volatile material was removed by evaporation and the residuewas purified by flash chromatography on silica gel eluting with 10-30%ethyl acetate/hexane to give the title compound (4.5 g) as a solid. NMR(CDCl₃) 2.52 (s, 3H), 7.03-7.08 (m, 1H), 7.3 (d, 2H), 7.36-7.38 (m, 1H),7.44 (d 2H), 7.77 (d, 1H).

[0879] Method 28

[0880](R)-N-(2-Chloro4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0881] Triisopropylsilanethiol (2.8 ml) was added to a stirredsuspension of sodium hydride (60% mineral oil dispersion, 0.53 g) inanhydrous THF (40 ml) cooled to 1° C. under argon. After 15 minutes atthis temperature tetrakis(triphenylphosphine)palladium (0) (1.21 g) wasadded and this solution was added to(R)-N-(2-chloro4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 197) (5.2 g) in anhydrous toluene (40 ml) and the mixture washeated to 85° C. for 2 hours. The mixture was allowed to cool to ambienttemperature, ethyl acetate (200 ml) was added and the mixture was washedwith brine (100 ml) and dried. Volatile material was removed byevaporation and the residue was purified on a silica gel flash columneluting with 1-20% ethyl acetate/hexane to give the title compound (6.51g) as a gum. NMR (CDCl₃) 1.07-1.1 (d, 18H), 1.20-1.28 (m, 3H), 1.74 (s,3H), 3.64 (s, 1H), 7.39-7.42 (m, 1H), 7.53 (s, 1H), 8.23 (d, 1H), 8.81(s, 1H); MS (ESP⁻): 454.

[0882] Method 29

[0883] 2-Chloro-4-benzylnitrobenzene

[0884] Sodium borohydride (1.45 g) was added to a solution of3-chloro-4-nitrobenzophenone (2.0 g) (prepared as described by R. B.Davis and J. D. Benigni, J. Org. Chem., 1962, 27, 1605) in ethanol andthe mixture was stirred for 18 hours. Volatile material was removed byevaporation and the residue was suspended in water (100 ml) andcautiously acidified with dilute aqueous hydrochloric acid (50 ml) andstirred a further 2 hours. The reaction mixture was basified with 2Maqueous sodium hydroxide solution and extracted with DCM. The extractswere combined, dried and concentrated by evaporation to give an oil.This was dissolved in TFA (12.1 ml) with cooling with an ice bath thentreated dropwise with triethylsilane (5.05 ml) and stirred overnight.The reaction mixture was poured onto aqueous sodium carbonate solutionand extracted with DCM. The extracts were combined, dried and evaporatedto give an oil which was purified by chromatography eluting with 20-50%ethyl acetate/hexane to give the title compound (0.60 g) as an oil. NMR(CDCl₃): 4.0 (s, 3H), 7.1-7.4 (m, 8H); MS (CI): 247 (M⁺).

[0885] Method 30

[0886] 2-Chloro-4-benzylaniline

[0887] A solution of 2-chloro-4-benzylnitrobenzene (Method 29) (0.60 g)in ethyl acetate was treated with 10% Pd/C (0.06 g) under argon. Themixture was then stirred under a hydrogen atmosphere for 10 hours. Themixture was filtered under argon and extracted with aqueous hydrochloricacid (50% v/v. 50 ml). The aqueous layer was separated, basified with 2Maqueous NaOH and extracted with ethyl acetate to give the title compoundas an oil (0.237 g).

[0888] NMR: 3.6 (s, 2H), 5.1 (brs 2H), 6.7 (d, 1H), 6.9 (dd, 1H), 7.0(d, 1H), 7.1-7.3 (m, 5H); MS (CI): 218 (M⁺)

[0889] Methods 31-32

[0890] Following the procedure of Method 30 and using the appropriatestarting materials the following compounds were prepared. Meth CompoundNMR MS SM 31 3-chloro-4-[di- 1.33(s, 18H), 341 Meth 45(t-butyloxy-carbonyl)- 5.42(s, 2H), 6.48(dd, amino]aniline 1H), 6.62(s,1H), 6.89(d, 1H) 32 (R)-N-(2-Chloro- 1.78(s, 3H), 325 Meth 244-amino-phenyl)- 2.15(s, 3H), 5.46(brs, 2-acetoxy-2-methyl- 2H), 6.50(d,1H), 3,3,3-trifluoro- 6.64(s, 1H), 6.80(d, propanamide 1H), 9.53(s, 1H)

[0891] Method 33

[0892]N-[2-Chloro-4-phenylsulphonylphenyl]-2-acetoxy-2-methylpropanamide

[0893] 2-Chloro-4-phenylsulphanylaniline (Method 5) was acylated with2-acetoxy-2-methylpropanoyl chloride by the procedure of Method 23 thenthe crude product was oxidised by the procedure of Example 114 to givethe title compound (in 91% yield) as a gummy solid.

[0894] NMR 1.57 (s, 6H), 2.05 (s, 3H), 7.6-7.75 (m, 4H), 7.8 (d, 1H),7.92 (dd, 1H), 8.0 (apparent d, 2H), 8.08 (d, 1H), 9.4 (s, 1H).

[0895] Method 34

[0896] (R)-N-[2-Chloro4-44-ureidophenylsulphanyl}phenyl]-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide

[0897] Water (0.34 ml), acetic acid (0.54 ml) and sodium cyanate (0.104g dissolved in 0.3 ml of water) were added to a solution of(R)-N-[2-chloro-4-{4-aminophenylsulphanyl}phenyl]-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide(0.432 g) (Method 22) in THF (0.8 ml. The mixture was stirred for 2hours then diluted with water (5 ml) and extracted with ethyl acetate(2×20 ml). The extracts were poured onto a Varian Chem Elut column andeluted with ethyl acetate. Volatile material was removed by evaporationand the residue was triturated with ether to give the title compound(0.31 g) as a solid. NMR: 1.8 (s, 3H), 2.2 (s, 3H), 5.9 (s, 2H), 7.1 (s,3H), 7.4 (d, 2H), 7.5 (d, 2H). 8.8 (s, 1H), 9.9 (s, 1H); MS (ESP⁻): 474.

[0898] Method 35

[0899] Following the procedure of Method 34 and using the appropriatestarting materials the following compound was prepared. Meth Compound MSSM 35 (R)-N-[2-Chloro-4-{2- 476 Meth ureidophenylsulphanyl}phenyl]- (M +H)⁺ 36 2-acetoxy-2-methyl-3,3,3- trifluoropropanamide

[0900] Methods 36-40

[0901] The indicated starting material was coupled with an appropriatethiol or halide using the method of Example 250, acylated using theprocedure of Method 17 then reduced by the procedure of Method 10 togive the following compounds. Meth Compound NMR MS SM 36(R)-N-[2-Chloro-4-{2-amino- 431 Ex 210 phenylsulphanyl}phenyl]-2-acetoxy-2-methyl-3,3,3- trifluoropropanamide 37(R)-N-[2-Chloro-4-{3-amino- 1.8(s, 13H), 2.2(s, 431 Ex 210phenylsulphanyl}phenyl]-2- 3H), 5.3(s, 2H), 6.5(t,acetoxy-2-methyl-3,3,3- 2H), 6.6(s, 1H), 7.0(t, trifluoropropanamide1H), 7.2(m, 3H), 9.9(s, 1H)  38¹ (R)-N-[2-Fluoro-4-{4-amino- 1.8(s, 3H),2.2(s, 3H), 415 2-fluoro-4- phenylsulphanyl}phenyl]-2- 5.6(s, 2H),6.6(d, 2H), iodoaniline acetoxy-2-methyl-3,3,3- 6.8(m, 2H), 7.1(t, 1H),trifluoropropanamide 7.2(d, 2H), 9.9(s, 1H)   39^(1,2)(R)-N-[2-Fluoro-4-{4- 1.8(s, 3H), 2.2(s, 3H), 445 2-fluoro-4-nitrophenylsulphanyl}phenyl]- 7.4(m, 4H), 7.6(d, iodoaniline2-acetoxy-2-methyl-3,3,3- 1H), 8.2(d, 2H), 10.12 trifluoropropanamide(s, 1H)   40^(2,3) (R)-2,3,4,5-H₄-3-[2-Chloro-4- (CDCl₃) 1.9(s, 3H), 3.9415 Ex 197 (4-aminophenylsulphanyl) (s, 2H), 6.7(d, 2H), 7.1phenyl]-2,4-dioxo-5-methyl- (m, 3H), 7.4(d, 2H) 5-trifluoromethyloxazole

[0902] Method 41

[0903](R)-N-[2-Chloro-4-{4-(2-morpholinoacetylamino)phenysulphanyl}phenyl]-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide

[0904] Following the procedure of Example 353 except that morpholine wasused in place of aqueous dimethylamine, the title compound was obtained(0.25 g) as a foam. NMR: 1.8 (s, 3H), 2.2 (s, 3H), 3.1 (s, 2H), 3.3 (s,4H), 3.6 (m, 4H), 7.1 (s, 2H), 7.2 (s, 1H), 7.4 (d, 2H), 7.7 (d, 2H),9.9 (s, 2H); MS (ESP⁻): 558.

[0905] Method 42

[0906](R)-2,3,4.5-H₄-3-{2-Chloro-4-[4-(3-ethylureido)phenylsulphanyl]phenyl}-2,4-dioxo-5-methyl-5-trifluoromethyloxazole

[0907] Ethyl isocyanate (0.062 ml) was added to a solution of(R)-2,3,4,5-H₄-3-[2-chloro-4-(4-aminophenylsulphanyl)phenyl]-2,4-dioxo-5-methyl-5-trifluoromethyloxazole(Method 40) (0.3 g) in anhydrous ether (0.5 ml) and THF (2 ml) and themixture was stirred for 24 hr. Volatile material was removed byevaporation and the residue was purified by chromatography on a silicagel Mega Bond Elut column eluting with eluting with 5-60% ethylacetate/hexane to give the title compound (0.29 g) as a gummy solid.NMR: 1.8 (q, 2H), 2.0 (s, 3H), 3.1 (m, 3H), 6.1 (t, 1H), 7.2 (d, 2H),7.5 (d, 2H), 7.6 (d, 2H), 7.6 (d, 1H), 8.7 (s, 1H); MS (ESP⁻): 486.

[0908] Methods 43-44

[0909] Following the procedure of Method 42 and using the appropriatestarting materials the following compounds were prepared. Meth CompoundNMR MS SM 43 (R)-N-[2-Chloro- 1.3(s, 9H), 1.8(s, 3H), 530 Meth4-{4-(3-t-butyl- 2.2(s, 3H), 6.1(s, 1H), 12 ureido)phenyl- 7.1(s, 3H),7.4(d, 2H), sulphanyl}- 7.5(d, 2H), 8.5(s, 1H), phenyl]-2-acetoxy-2-9.9(s, 1H) methyl-3,3,3- trifluoro- propanamide 44 (R)-N-[2-Chloro-1.8(s, 3H), 2.2(s, 3H), 550 Meth 4-{4-(3-phenyl- 7.0(t, 1H), 7.1(d, 3H),12 ureido)phenyl- 7.3(t, 2H), 7.4(m, 4H), sulphanyl}phenyl]- 7.6(d, 2H),8.7(s, 1H), 2-acetoxy-2-methyl- 8.9(s, 1H), 9.9(s, 1H) 3,3,3-trifluoro-propanamide

[0910] Method 45

[0911] N,N-di-(t-Butyloxycarbonyl)-2-chloro4-nitroaniline

[0912] 2-Chloro-4-nitroaniline (1.726 g) was added to an ice-cooledsolution of di-t-butyl dicarbonate (2.401 g) in THF (50 ml). The mixturewas allowed to warm to room temperature. 4-Dimethylaminopyridine (0.01g) was added and the solution was stirred for a further 19 hours thenheated at 60° C. for 26 hours. Volatile material was removed byevaporation and the residue was partitioned between water (100 ml) andDCM (200 ml). The organic phase was washed with brine then dried andreconcentrated. The residue was purified by chromatography on silica togive the title compound (1.261 g) as a solid. NMR: 1.35 (s, 18H), 7.78(d, 1H), 8.22 (dd, 1H), 8.42 (s, 1H); MS: 372 (M⁺).

[0913] Method 46

[0914]3-chloro-4-[di-(t-butyloxy-carbonyl)amino]-1-(2-nitroanilino)phenyl

[0915] A mixture of 1,1′-bis(diphenylphosphino)ferrocene (0.1 g) andpalladium (II) acetate (0.028 g) in toluene (4 ml) was stirred at 100°C. under Argon for one hour. This was added to a mixture of driedcaesium carbonate (0.912 g),3-chloro-4-[di-(t-butyloxy-carbonyl)amino]aniline (Method 31) (0.822 g)and 2-bromo-l-nitrobenzene (0.404 g) in toluene (7 ml). The mixture wasstirred for 23 hours at 100° C. under argon then cooled, filtered andconcentrated by evaporation. The residue was dissolved in ethyl acetate(75 ml), washed with 1M aqueous hydrochloric acid (2×5 ml), water (25ml) and brine (25 ml) then dried. Volatile material was removed byevaporation and the residue was purified by chromatography on a silicagel Mega Bond Elut column eluting with 10% ethyl acetate/hexane to givethe title compound (0.889 g) as a gum. NMR: 1.40 (s, 18H), 7.00 (t, 1H),7.27 (m, 2H). 7.36 (d, 1H), 7.45 (s, 1H), 7.58 (t, 1H), 8.10 (d, 1H),9.28 (s, 1H); MS (ESP⁻): 46

[0916] Method 47

[0917] 2-chloro-4-(2-nitroanilino)aniline

[0918] TFA (3 ml) was added to a solution of3-chloro4-[di-(t-butyloxy-carbonyl)amino]-1-(2-nitroanilino)phenyl(Method 46) (0.88 g) in DCM (15 ml). After 2 hours the solution wasevaporated to dryness. The residue was dissolved in ethyl acetate (100ml), washed with 1M aqueous sodium hydroxide (50 ml), water (50 ml) andbrine (50 ml) then dried and reconcentrated to give the title compound(0.45 g) as a solid; MS (ESP⁺): 264 (M+H)⁺.

[0919] Method 48

[0920](R)-N-[2-Chloro-4-(phenylsulphanyl)phenyl]-2-(t-butoxycarbonylamino)propanamide

[0921] (Based on the procedure of Villeneuve, G. B. et al., TetrahedronLetters (1997), 38 (37), 6489.)

[0922] Triphenylphosphine (0.0.612 g) was added to a cooled (−78° C.)solution of hexachloroacetone (0.18 ml) andN-t-butyloxycarbonyl-2-methylalanine (0.441 g) in dry DCM (15 ml) underargon. The resulting mixture was stirred at low temperature for 20minutes. Then 2-chloro-4-(phenylsulphanyl)aniline (0.5 g) (Method 5) anddry triethylamine (0.33 ml) were added. The resulting mixture was slowlywarmed to room temperature, under argon, before being stirred for 1 hourat room temperature. Saturated aqueous ammonium chloride solution (15ml) was added and the mixture was extracted with DCM (2×50 ml). Theorganic extracts were combined, washed with brine and dried. Volatilematerial was removed by evaporation and the residue was purified bychromatography on a silica gel column eluting with 2% ethyl acetate/DCMto give the title compound. NMR (CDCl₃): 1.40-1.45 (m, 12H), 4.29-4.40(m, 1H), 4.86-4.95 (m, 1H), 7.20-7.40 (m, 7H), 8.30-8.38 (m, 1H), 8.64(brs, 1H);

[0923] MS (ESP⁻): 405.

[0924] Method 49

[0925] (S)-2-Acetoxy-2-methyl-3,3,3-trifluoropropanoyl chloride

[0926] Acetyl chloride (11.7 ml) was added dropwise to a stirredsolution of (R)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (10 g)(Method 9) in toluene (100 ml) cooled in an ice bath. The mixture wasthen heated to 80° C. and the suspension dissolved to give a clearsolution. After 2 hours the reaction mixture was cooled and thenconcentrated to give an oil. This oil was then redissolved in DCM (140ml) and DMF (4 drops) was added followed by oxalyl chloride (6 ml). Thesolution bubbled vigorously and the reaction mixture was left to stirfor 15 hours. The resultant solution of the title compound was useddirectly without further purification.

[0927] Method 50

[0928](R)-N-(2-Chloro-4-{3-t-butoxy-2-hydroxypropylamino}phenyl)-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide

[0929] t-Butyl glycidyl ether (0.19 ml) and copper(II)trifluoromethanesulphonate (0.018 g) were added to a solution of(R)-N-(2-chloro-4-aminophenyl)-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide(0.325 g) (Method 32) in diethyl ether (5 ml). The mixture was stirredfor 40 hours then volatile material was removed by evaporation and theresidue was purified by chromatography to give the title compound (0.141g) as a foam; MS (ESP⁻): 453.

[0930] Method 51

[0931] 3.4-Difluorobenzenethiol

[0932] A solution of triphenylphosphine (37.0 g) and DMF (2 ml) in DCM(100 ml) was maintained at 20° C. with an ice bath during addition of3,4-difluorobenzenesulphonyl chloride (10 g). The mixture was stirred atroom temperature for 2 hours then aqueous hydrochloric acid (50 ml of a1M solution) was added. The mixture was stirred for a further 1 hour.The organic layer was separated, dried and the solvent removed byevaporation to give the title compound as an oil which was used withoutpurification.

[0933] Method 52

[0934] 2-(4-Triisopropylsilylsulphanylphenyl)pyrimidine

[0935] Tetrakis(triphenylphosphine)palladium(0) (0.28 g) was added to asolution of 2-(4-bromophenyl)pyrimidine (1.751 g) (prepared as describedin U.S. patent application Ser. No. 96-692869 (CA 129:136175)) intoluene (40 ml) and the mixture was heated at 80° C. under argon for onehour. Trisopropylsilanethiol (2.14 ml) was added dropwise to a stirredsuspension of sodium hydride (0.4 g of a 60% dispersion in oil) in dryTHF (20 ml) cooled with ice/water. The cooling bath was removed and themixture was stirred for 10 minutes to give a clear solution. Thissolution was added to the reagents in toluene and the mixture wasstirred under reflux for 16 hours then cooled. Water (50 ml) was addedand the mixture was extracted with ethyl acetate (3×50 ml). The extractswere combined, washed with brine (100 ml) and dried. Volatile materialwas removed by evaporation and the residue was purified bychromatography eluting with 20% ethyl acetate/hexane to give the titlecompound (1.49 g) as a solid; NMR (at 343K): 0.86-1.07 (m, 21H), 7.4 (t,1H), 7.7 (m, 2H), 8.39 (m, 2H), 8.87 (m, 2H); MS (EI): 344 (M⁺).

[0936] Method 53

[0937] 6-Iodoquinazolinedione

[0938] A mixture of 2-amino-5-iodobenzoic acid (3.5 g) and urea (1.56 g)in NMP (15 ml) was heated at 160° C. for 6 hours then cooled. Water (200ml) was added and the resultant precipitate was collected, washed withwater and dried to give the title compound (3.35 g) as a solid. MS(CI⁺): 289 (M+H)⁺.

[0939] Method 54

[0940] 1,3-Dimethyl-6-iodoquinazolinedione

[0941] Sodium hydride (0.24 g of a 60% dispersion in oil) was addedportionwise to a stirred solution of 6-iodoquinazolinedione (0.58 g)(Method 53) and iodomethane (0.63 ml) in DMF (10 ml). The mixture wasstirred for 1 hour then added cautiously to saturated aqueous ammoniumchloride solution (200 ml). Extraction with ethyl acetate followed byrecrystallization from ethanol plus a little chloroform gave the titlecompound (0.48 g) as a solid. MS (CI⁺): 317 (M+H)⁺.

[0942] Method 55

[0943]N-[2-Fluoro-4-(4-methylsulphanylphenylsulphanyl)phenyl]-2-t-butyldimethylsilyloxy-2-trifluoromethyl-3,3,3-trifluoropropanamide

[0944] To a stirred solution of2-t-butyldimethylsilyloxy-2-trifluoromethyl-3,3,3-trifluoropropanoicacid, t-butyldimethylsilyl ester (Method 56) (1.05 g) in DCM (10 ml) wasadded DMF (2 drops) and oxalyl chloride (0.23 ml). The reaction mixturewas stirred for 17 hours and was then added to a solution of2-fluoro-4-(4-methylsulphanylphenylsulphanyl) aniline (Method 6) (0.63g) in DCM (5 ml) and pyridine (0.22 ml). The reaction mixture wasstirred at ambient temperature for 48 hours, evaporated under reducedpressure and the residue purified by chromatography on a silica gel MegaBond Elut column eluting with 5-20% ethyl acetate/iso-hexane to give thetitle compound (0.278 g) as a yellow gum. NMR (CDCl₃): 0.29 (s, 6H),0.98 (s, 9H), 2.48 (s, 3H), 6.96-7.0 (m, 1H), 7.06 (d, 1H), 7.2 (d, 2H),7.31 (d, 2H), 8.23 (t, 1H), 8.62 (brs, 1H).

[0945] Method 56

[0946]2-t-Butyldimethylsilyloxy-2-trifluoromethyl-3,3,3-trifluoropropanoicacid, t-butyldimethylsilyl ester

[0947] A stirred solution of2-hydroxy-2-trifluoromethyl-3,3,3-trifluoropropanoic acid (2.26 g) inanhydrous DMF (11 ml) under argon was treated with t-butyldimethylsilylchloride (3.37 g) followed by imidazole (3.02 g). The reaction mixturewas stirred for 17 hours then extracted with iso-hexane (3×100 ml) andthe organic phase washed with aqueous sodium hydrogen carbonate (2×200ml) and dried. Volatile material was removed by evaporation to give thetitle compound (3.09 g) as an oil. NMR (CDCl₃): 0.01 (s, 6H), 0.87 (s,9H); MS (EI+) 383 (M−C₄H₉).

[0948] Method 57

[0949](R)-N-[2-(2-Trimethylsilylethynyl)-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0950] Bis(triphenylphosphine)palladium(II) chloride (0.01 g),triphenylphosphine (0.0038 g), trimethylsilylacetylene (0.17 ml),triethylamine (0.16 ml) and copper(I) iodide (0.0013 g) were added to asolution of(R)-N-[2-bromo-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 140) (0.311 g) in anhydrous THF (10 ml) under argon. Themixture was heated at 50° C. for 3 hours then morebis(triphenylphosphine) palladium(11) chloride (0.01 g) andtrimethylsilylacetylene (0.17 ml) were added and heating was continuedfor a further 3 hours. The reaction mixture was allowed to cool, ethylacetate (50 ml) was added and the mixture was filtered through a pad ofdiatomaceous earth which was washed with ethyl acetate (3×20 ml). Thefiltrates were combined and volatile material was removed byevaporation. The residue was purified by chromatography eluting with10-40% ethyl acetate/iso-hexane to give the title compound (in 89%yield) as a solid. NMR (CDCl₃): 0.29 (s, 9H), 1.74 (s, 3H), 3.05 (s,3H), 3.69 (s, 1H), 7.88-7.92 (m, 1H), 8.02 (d, 1H), 8.05-8.13 (m, 4H),8.61 (d, 1H), 9.46 (s, 1H); MS (ESP⁻): 546.

[0951] Method 58

[0952] 5-Iodo-2H-benzimidazol-2-one

[0953] A mixture of iodine monochioride and 2H-benzimidazole-2-one (0.67g) (Method 59) in glacial acetic acid (8 ml) was heated to 80° C. for 1hour then cooled. The mixture was partitioned between saturated aqueoussodium sulphite solution and DCM. The organic layer was evaporated todryness then redissolved in ethyl acetate. The aqueous layer wasextracted with ethyl acetate then all ethyl acetate extracts werecombined and washed with saturated aqueous sodium hydrogen carbonatesolution, water and brine. The organic extracts were passed through aVarian Chem Elut column and washed through with ethyl acetate. Volatilematerial was removed by evaporation to give the title compound (0.36 g)as a solid which was used without further purification. MS (ESP⁺): 261(M+H)⁺.

[0954] Method 59

[0955] 2H-Benzimidazol-2-one

[0956] A solution of phenylene diamine 6.48 g in dry THF (150 ml) wascooled to 5° C. A suspension of 1,1-carbonyldiimidazole (10.7 g) in THF(100 ml) was added to this solution over 15 minutes keeping thetemperature below 10° C. The mixture was stirred for 16 hours and theresultant solid was collected and dried to give the title compound (4.5g); NMR: 6.9 (s, 4H), 10.5 (s, 2H); MS (ESP⁺): 135 (M+H)⁺.

[0957] Methods 60-62

[0958] Following the procedure of Example 197 and using the appropriatestarting material the following compounds were prepared. Meth CompoundINMK MS SM 60 (R)-N-(2-Chloro-4-nitrophenyl)- 1.64(s, 3H), 8.13(s, 1H),311 2-Chloro-4- 2-hydroxy-2-methyl-3,3,3- 8.28(d, 1H), 8.39(d, 1H),nitroaniline trifluoropropanamide 8.45(s, 1H), 10.0(s, 1H) 61(R)-N-(2-Methoxy-4- (CDCl₃) 1.75(s, 3H), 4.07 307 2-Methoxy-nitrophenyl)-2-hydroxy-2- (s, 3H), 7.72-7.75(m, 1H), 4-nitroanilinemethyl-3,3,3- 7.88-7.97(m, 1H), 8.50- trifluoropropanamide 8.58(m, 1H),9.27(brs, 1H) 62 (R)-N-(2-Methyl-4-nitrophenyl)- (CDCl₃) 1.77(s, 3H),2.39 291 2-Methyl-4- 2-hydroxy-2-methyl-3,3,3- (s, 3H), 3.5(s, 1H),8.09- nitroaniline trifluoropropanamide 8.15(m, 2H), 8.30-8.38(m, 1H),8.65(brs, 1H)

[0959] Method 63

[0960](R)-N-[2-Chloro-4-(2-fluorophenylsulphonyl)phenyl[-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0961] m-Chloroperoxybenzoic acid (55%, 2.39 g) was added to a solutionof(R)-N-[2-chloro-4-(2-fluorophenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 187) (0.906 g) in DCM (60 ml) and the mixture was stirred atambient temperature for 6 hours. The mixture was then washed withsaturated aqueous sodium hydrogen carbonate solution (3×100 ml), water(100 ml) and brine then dried. Volatile material was removed byevaporation and the residue was triturated with hexane to give the titlecompound (0.808 g) as a solid. Mp 90-92° C.; NMR (CDCl₃): 1.75 (s, 3H),3.65 (brs, 1H), 7.15 (t, 1H), 7.35 (t, 1H), 7.60 (m, 1H), 7.95 (d, 1H),8.10 (m, 2H), 8.60 (d, 1H), 9.30 (brs, 1H); MS (ESP⁻): 424.

[0962] Methods 64-66

[0963] Following the procedure of Method 63 and using the appropriatestarting material the following compounds were prepared. Meth CompoundNMR SM 64 +TL,4(R)-N-[2-Fluoro-4-{2-fluoro- 1.59(s, 3H), 7.38-7.55(m,2H), Ex 195 phenylsulphonyl}phenyl]-2-hydroxy- 7.7-7.9(m, 4H), 8.05(q,2H), 2-methyl-3,3,3-trifluoropropanamide 9.85(brs, 1H) 65(R)-N-[2-Fluoro-4-(4-nitrophenyl- 1.58(s, 3H), 7.75(s, 1H), 7.87 Ex 176sulphonyl)phenyl]-2-hydroxy-2- (dd, 1H), 8.0(dd, 1H), 8.08(d,methyl-3,3,3-trifluoropropanamide 1H), 8.25(d, 2H), 8.4(d, 2H), 9.9(brs,1H) 66 (R)-N-[2-Chloro-4-(3,4- (CDCl₃) 1.75(s, 3H), 7.25-7.35 Ex 276difluorophenylsulphonyl)phenyl]-2- (m, 1H), 7.4(t, 1H), 7.5-7.6(m,hydroxy-2-methyl-3,3,3- 1H), 7.65-7.9(m, 2H), 8.0(m,trifluoropropanamide 1H), 8.1(m, 1H), 8.6(d, 1H), 9.3(brs, 1H)

[0964] Methods 67-68

[0965] Following the procedure of Method 16 and using the appropriatestarting material the following compounds were prepared. Meth CompoundNMR SM 67 +TL,4(R)-N-[2-Chloro-4-{2-nitrophenyl- 1.6(s, 3H), 8.0(m, 5H),8.1(s, Ex 264 sulphonyl}phenyl]-2-hydroxy-2- 1H), 8.4(m, 2H), 9.9(s, 1H)methyl-3,3,3-trifluoropropanamide 68 (R)-N-[2-Chloro-4-{3-nitrophenyl-(CDCl₃) 2.75(s, 3H), 3.55(s, 1H), Ex 331 sulphonyl}phenyl]-2-hydroxy-2-7.75(t, 1H), 7.9(dd, 1H), 8.1(s, methyl-3,3,3-trifluoropropanamide 1H),8.25(d, 1H), 8.45(d, 1H), 8.7 (d, 1H), 8.75(s, 1H), 9.3(brs, 1H)

[0966] Method 69

[0967](R)-N-[2-Chloro-4-(4-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0968] Hydrogen peroxide (0.3 ml of a 30 wt. % solution in water) wasadded to a solution of(R)-N-[2-chloro-4-(4-fluorophenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Example 188) (0.283 g) in glacial acetic acid (1.0 ml) and the mixturewas stirred and heated at 100° C. for 80 minutes then allowed to cool.Ethyl acetate (40 ml) was added and the solution was washed with water(20 ml), saturated aqueous sodium hydrogen carbonate solution (20 ml)and brine and then dried. Volatile material was removed by evaporationand the residue was purified by chromatography on a silica gel Mega BondElut column eluting with 0-25% ethyl acetate/hexane to give the titlecompound (0.261 g; 72%) as a solid Mp 131-133 ° C.; NMR: 1.6 (s, 3H),7.46 (t, 2H), 8.0 (dd, 1H), 8.08 (m, 2H), 8.15 (d, 1H), 8.3 (d, 1H),9.85 (brs, 1H); MS (ESP⁺): 426 (M+H)⁺.

[0969] Method 70-72

[0970] Following the procedure of Method 69 and using the appropriatestarting material the following compounds were prepared. Meth CompoundNMR SM 70 +TL,4(R)-N-[2-Chloro-4-{3-fluoro- +TL,17(CDCl₃) 1.75(s, 3H),3.75(s, 1H), Ex 253 phenylsulphonyl}phenyl]-2- 7.10(dd, 1H), 7.30(dd,1H), 7.50- hydroxy-2-methyl-3,3,3- 7.70(m, 1H), 7.90(d, 1H), 8.05-8.10trifluoropropanamide (m, 2H), 8.65(d, 1H), 9.40(s, 1H) 71(R)-N-[2-Fluoro-4-{4-fluoro- 1.73(s, 3H), 4.26(s, 1H), 7.18(t, Ex 193phenylsulphonyl}phenyl]-2- 2H), 7.8(t, 2H), 7.89-7.94(m, 2H),hydroxy-2-methyl-3,3,3- 8.56(t, 2H), 9.0(s, 1H) trifluoropropanamide 72(R)-N-[2-Chloro-4-{3-chloro- (CDCl₃) 1.75(s, 3H), 5.1(brs, 1H), Ex 2754-fluorophenylsulphonyl} 7.2-7.3(m, 1H), 7.6-7.9(m, 2H),phenyl]-2-hydroxy-2-methyl- 7.95-8.0(m, 2H), 8.65(d, 1H), 9.53,3,3-trifluoropropanamide (brs, 1H)

[0971] Method 73

[0972] (R)-N-(2-Chloro-4-chlorosulphonylphenyl)-2-hydroxy-2-methyl-3,33-trifluoropropanamide

[0973](R)-N-(2-Chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide(Method 74) (13.8 g, 52 mmol) was added in portions to a cooled (0° C)solution of chlorosulphonic acid (25 ml) over 15 mins and then themixture was heated to 85° C. After 4.5 h the reaction mixture was cooledin an ice bath and then poured very slowly onto a stirred ice-watermixture. After stirring for 15 mins, the mixture was extracted withethyl acetate (2×100 ml) and the combined organic layer washed withbrine, dried and concentrated to yield a brown oil. This oil waspurified by flash column chromatography using 10: 1, iso-hexane: ethylacetate to yield the title compound as a pale yellow solid (11 g, 30mmol). NMR: 1.6 (s, 3H), 7.55 (dd, 1H), 7.6 (d, 1H), 7.95 (d, 1H), 9.7(brs, 1H); MS: 364.

[0974] Method 74

[0975](R)-N-(2-Chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

[0976] Acetyl chloride (11.7 ml, 164 mmol) was added dropwise to astirred solution of the (R)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoicacid (Method 9) (10 g, 63 mmol) in toluene (100 ml) cooled in an icebath. The mixture was then heated to 80° C. and the suspension dissolvedto yield a clear solution. After 2 h the reaction mixture was cooled andthen concentrated to yield a slight brown oil. This oil was thenredissolved in DCM (140 ml) and DMF (4 drops) was added followed byoxalyl chloride (6 ml, 69 mmol). The solution bubbled vigorously and thereaction mixture was left to stir. After 15 h, this reaction mixture wasadded slowly to a stirred solution of 2-chloroaniline (8.7 g, 68 mmol)and pyridine (5.5 ml, 68 mmol) in DCM (150 ml). After 15 h stirring atroom temperature, the resultant mixture was concentrated and the residuedissolved in methanol (500 ml). A solution of lithium hydroxidemonohydrate (7.8 g, 0.19 mol) in water (120 ml) was then added and themixture was stirred for 4 h. The mixture was then concentrated and theresidue acidified to pH 2 (by addition of concentrated hydrochloricacid). Ethyl acetate(150 ml) was added and the mixture washed with water(2×100 ml) and brine, dried and evaporated to dryness. The residue waspurified by flash column chromatography using 6:1, iso-hexane:ethylacetate to yield the title compound as a white solid (13.8 g, 52 mmol).NMR: 1.6 (s, 3H), 7.1-7.25 (m, 1H), 7.3-7.4 (m, 1H), 7.55 (dd, 1H), 7.8(s, 1H), 8.0 (dd, 1H), 9.7 (brs, 1H); MS: 266.

[0977] Method 75

[0978] Following the procedure of Method 63 and using the appropriatestarting material the following compounds were prepared. Meth CompoundNMR and MS SM 75 (R)-N-[2-Chloro-4-(4-fluoro- (CDCl₃): 1.74(s, 3H), Ex188 phenylsulphinyl)phenyl]-2- 4.16 and 4.24 hydroxy-2-methyl-3,3,3- (2x br s, 1H), trifluoropropanamide 7.19(t, 2H), 7.49(d, 1H), 7.63(dd,2H), 7.7(d, 1H), 8.52(m, 1H), 9.2(br s, 1H); MS 408

EXAMPLE 429

[0979] The following illustrate representative pharmaceutical dosageforms containing the compound of formula (I), or a pharmaceuticallyacceptable salt thereof (hereafter compound X), for therapeutic orprophylactic use in humans: (a) Tablet I mg/tablet Compound X 100Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste2.25 (5% w/v paste) Magnesium stearate 3.0 (b) Tablet II mg/tabletCompound X 50 Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Maizestarch 15.0 Polyvinylpyrrolidone 2.25 (5% w/v paste) Magnesium stearate3.0 (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25Croscarmellose sodium 4.0 Maize starch paste 0.75 (5% w/v paste)Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg/ml) Compound X5.0% w/v      1 N Sodium hydroxide 15.0% v/v     solution 0.1 NHydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5%w/v      Water for injection to 100% (f) Injection II (10 mg/ml)Compound X 1.0% w/v      Sodium phosphate BP 3.6% w/v      0.1 N Sodiumhydroxide 15.0% v/v     solution Water for injection to 100% (1 mg/ml.buffered (g) Injection III to pH6) Compound X 0.1% w/v      Sodiumphosphate BP  2.26% w/v     Citric acid  0.38% w/v     Polyethyleneglycol 400 3.5% w/v      Water for injection to 100%

What is claimed is:
 1. The use of compounds of the formula (1):

wherein: ring C is as defined in (a) or (b); R¹ is as defined in (c) or(d); n is 1 or2; R² and R³ are as defined in (e) or (f); A-B is asdefined in (g) or (h) and R⁴ is as defined in (i) or (j) wherein (a)ring C is phenyl or carbon-linked heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl; wherein said phenyl orheteroaryl is substituted on carbon at one or both positions meta to theposition of A-B attachment or on carbon at the position para to theposition of A-B attachment by P¹ or p² (wherein P¹ and p² are as definedhereinafter), and further, wherein said phenyl or heteroaryl isoptionally substituted on carbon at any remaining meta position(s) orpara position by P¹ or P³, (wherein P¹ and P³ are as definedhereinafter); (b) ring C is selected from the following five groups: (i)phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl isunsubstituted except by (R¹)_(n) wherein R¹ and n are as definedhereinafter; (ii) a carbon-linked triazine optionally substituted on aring carbon at a position meta or para to A-B attachment by 1substituent selected from P¹, p², p³ and p⁴, wherein P¹, p², p³ and P⁴are as defined hereinafter; (iii) a 6-membered carbon-linked heteroarylgroup containing 1-3 nitrogen atoms wherein one or more ring nitrogenatoms are oxidised to form the N-oxide, which heteroaryl group isoptionally substituted at any of the positions meta or para to A-Battachment by 1-3 substituents selected from P¹, P², P³ and P⁴, whereinP¹, P², P³ and P⁴ are as defined hereinafter; (iv) phenyl orcarbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyland pyridazinyl, wherein said phenyl or heteroaryl is substituted at aposition meta or para to A-B attachment by 1 substituent selected fromP³ and P⁴, wherein P³ and P⁴ are as defined hereinafter; and (v) phenylor carbon-linked heteroaryl selected from pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl issubstituted at any of the positions meta or para to A-B attachment by2-3 substituents selected from P¹, P², P³ and P⁴, provided that if oneor more of the substituents is P¹ or P² then at least one of the othersubstituents is P⁴, wherein P¹, P², P³ and P⁴ are as definedhereinafter; P¹ is cyano, trifluoromethyl, nitro, trifluoromethoxy ortrifluoromethylsulphanyl; P² is —Y¹Ar¹, wherein Ar¹ is selected from thegroup consisting of phenyl, a carbon-linked 6-membered heteroaryl ringcontaining 1-2 nitrogen atoms and a carbon-linked 5-membered heteroarylring containing 1-2 heteroatoms selected independently from O, N and S,wherein said phenyl or heteroaryl ring is optionally substituted atcarbon, with 1-4 substituents selected from Q¹, wherein Q¹ is as definedhereinafter; and Y¹ is selected from —CO—, —SO— and —SO₂—; P³ isC₁₋₄alkyl, haloC₂₋₄alkyl, C₁₋₄alkoxy, haloC₂₋₄alkoxy, C₂₋₄alkenyloxy,halo or hydroxy; P⁴ is selected from the following eight groups: 1)halosulphonyl, cyanosulphanyl; 2) —X¹—R⁵ wherein X¹ is a direct bond,—O—, —S—, —SO—, —SO₂—, —OSO₂—, —SO₂O—, —NR⁶—, —N⁺O⁻R⁶—, —CO—, —COO—,—OCO—, —CONR⁷—, —NR⁸CO—, —OCONR⁹—, —CONR¹⁰SO₂—, —NR¹¹SO₂—, —CH₂—,—NR¹²COO—, —CSNR¹³—, —NR¹⁴CS—, —NR¹⁵CSNR¹⁶—, NR¹⁷CONR¹⁸— or—NR¹⁹CONR²⁰SO₂— (wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently represents hydrogen orC₁₋₄alkyl which C₁₋₄alkyl may be optionally substituted by one or moregroups selected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R⁵ is selected from hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl which C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionally substitutedwith one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl with theproviso that P⁴ is not trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; 3)—X¹—C₁₋₆alkyl-X²—R²¹ wherein X¹ is as defined hereinbefore, X² is adirect bond, —O—, —S—, —SO—, —SO₂—, —OSO₂—, —SO₂O—, —NR²²—, —N⁺O⁻R²²—,—CO—, —COO—, —OCO—, —CONR²³—, —NR²⁴CO—, —NR²⁵COO—, —SO₂NR²⁶—, —NR²⁷SO₂—,—CH₂—, —SO₂NR²⁸CO—, —OCONR²⁹—, —CSNR⁺—, —NR⁻CS—, —NR³²CSNR³³—,—NR³⁴CONR³⁵—, —CONR³⁶SO₂—, —NR³⁷CONR³⁸SO₂—, —SO₂NR³⁹CONR⁴⁰— or—SO₂NR³⁹CNNR⁴⁰— (wherein R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰,R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹ and R⁴⁰, each independentlyrepresents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be as definedhereinbefore; optionally substituted by one or more groups selected fromhydroxy, amino halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy orC₁₋₃alkylsulphanyl) and R²¹ is hydrogen or C₁₋₄alkyl which C₁₋₄alkyl isoptionally substituted with one or more groups selected from hydroxy,amino, halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy andhydroxyC₁₋₆alkyl or R²¹ is R⁴¹ wherein R⁴¹ is phenyl or a 4-12 memberedheterocyclic moiety containing 1-4 heteroatoms selected independentlyfrom O, N and S which heterocylic moiety may be aromatic or non-aromaticand which phenyl or heterocylic moiety is optionally substituted by 1-6substituents selected from Q³ wherein Q³ is as defined hereinafter withthe proviso that P⁴ is not C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy orhaloC₁₋₄alkoxy: 4) —X¹—C₂₋₆alkenyl-X²—R²¹ wherein X¹, X² and R²¹ are asdefined hereinbefore with proviso that P⁴ is not C₂₋₄alkenyloxy; 5)—X¹—C₂₋₆alkynyl-X²—R²¹ wherein X¹, X² and R²¹ are as definedhereinbefore: 6) —X¹—C₃₋₇cycloalkyl-X²—R²¹ wherein X¹, X² and R²¹ are asdefined hereinbefore; 7) —X¹—C₁₋₆alkylC₃₋₇cycloalkyl-X²—R²¹ wherein X¹,X² and R²¹ are as defined hereinbefore; and 8) —Y²Ar² wherein Y² is X¹wherein X¹ is as defined hereinbefore and Ar² is selected from thefollowing six groups: (i) phenyl, a carbon-linked 6-membered heteroarylring containing 1-2 nitrogen atoms and a carbon-linked 5-memberedheteroaryl ring containing 1-2 heteroatoms selected independently fromO, N and S, wherein said phenyl or heteroaryl ring is substituted atcarbon, with 1-4 substituents selected from Q¹ and Q² including at leastone substituent selected from Q² wherein Q¹ and Q² are as definedhereinafter; (ii) a carbon-linked triazine or a carbon-linked 5-memberedheteroaryl ring containing 3-4 heteroatoms selected independently fromO, N and S; wherein said heteroaryl ring is optionally substituted with1-4 substituents selected from Q¹ and Q² wherein Q¹ and Q² are asdefined hereinafter; (iii) a 4-12 membered non-aromatic heterocyclicmoiety containing 1-4 heteroatoms selected independently from O, N and Swherein said heterocyclic moiety is optionally substituted with 1-6substituents selected from Q³ wherein Q³ is as defined hereinafter, withthe proviso that if Ar² is a nitrogen linked heterocyclic ring Y² is not—SO₂—; (iv) a 5-membered heteroaryl ring containing 1-4 heteroatomsselected independently from O, N and S, which heteroaryl ring containsat least one nitrogen atom substituted by a group selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, benzoyl orphenylsulphonyl and which heteroaryl ring is optionally substituted by1-3 substituents selected from Q³ wherein Q³ is as defined hereinafter;(v) a carbon linked 7-12 membered aromatic heterocyclic moietycontaining 1-4 heteroatoms selected independently from O, N and Swherein said heterocyclic moiety is optionally substituted with 1-6substituents selected from Q³ wherein Q³ is as defined hereinafter; and(vi) Ar¹ with the proviso that if Ar² has a value Ar¹ then Y² is not—CO—, —SO— or —SO₂—; Q¹ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₂₋alkenyloxy, cyano, nitro, halo ortrifluoromethylsulphanyl; Q² is selected from the following tengroups: 1) oxygen (forming an oxo group when linked to a ring carbon andforming an N-oxide when a ring nitrogen is oxidised); 2) halosulphonyl,cyanosulphanyl; 3) —X³—R⁵ wherein X³ is a direct bond, —O—, —S—, —SO—,—SO₂—, —OSO₂—, —SO₂O—, —NR⁴²—,—N⁺O⁻R⁴²—, —CO—, —COO—, —OCO—, —CONR⁴³—,—NR⁴⁴CO—, —NR⁴⁵COO—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂—, —CH₂—, —SO₂NR⁴⁸CO—,—OCONR⁴⁹—, —CSNR⁵⁰—, —NR⁵¹CS—, —NR⁵²CSNR⁵³—, —NR⁵⁴CONR⁵⁵—, —CONR⁵⁶SO₂—,—NR⁵⁷CONR⁵⁸SO₂—, —SO₂NR⁵⁷CNNR⁵⁸— or —SO₂NR⁵⁹CONR⁶⁰— (wherein R⁴², W⁴³,R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ R⁵⁶, R⁵⁷,R⁵⁸, R⁵⁹, and R⁶⁰ each independently represents hydrogen or C₁₋₄alkylwhich C₁₋₄alkyl may be optionally substituted by one or more groupsselected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R⁵ is as defined hereinbefore butwith the proviso that Q² is not trifluoromethylsulphanyl, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; 4) R⁴¹wherein R⁴¹ is as defined hereinbefore; 5) —X³—C₁₋₆alkyl-X²—R²¹ whereinX³, X² and R²¹ are as defined hereinbefore but with the proviso that Q²is not C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy or haloC₁₋₄alkoxy; 6)—X³-C₂₋₆alkenyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore but with the proviso that Q² is C₂₋₄alkenyloxy; 7)—X³—C₂₋₆alkynyl-X²—R²¹ wherein X³, X² and R²¹ are as definedhereinbefore; 8) —X³—C₃₋₇cycloalkyl-X²—R²¹ wherein X³, X² and R²¹ are asdefined hereinbefore; 9) —X³—C₁₋₆alkylC₃₋₇cycloalkyl-X²—R²¹ wherein X³,X² and R²¹ are as as defined hereinbefore; and 10) —X³—R⁴¹ wherein R⁴¹and X³ are as defined hereinbefore; Q³ is selected from the followingfour groups: 1) oxygen (forming an oxo group when linked to a ringcarbon and forming an N-oxide when a ring nitrogen is oxidised); 2)cyano, nitro or halo; 3) halosulphonyl, cyanosulphanyl; and 4) —X⁴—R⁶¹wherein X⁴ is a direct bond, —O—, —S—, —SO—, —SO₂—, —OSO₂—, —SO₂O—,—NR⁶²—, —N⁺O⁻R⁶²—, —CO—, —COO—, —OCO—, —CONR⁶³—, —NR⁶⁴CO—, —NR⁶⁵COO—,—SO₂NR⁶⁶—, —NR⁶⁷SO₂—, —CH₂—, —SO₂NR⁶⁸CO—, —OCONR⁶⁹—, —CSNR⁷⁰—, —NR⁷¹CS—,—NR⁷²CSNR⁷³—, —NR⁷⁴CONR⁷⁵—, —CONR⁷⁶SO₂—, —NR⁷⁷CONR⁷⁸SO₂—,—SO₂NR⁷⁹CNNR⁸⁰— or —SO₂NR⁷⁹CONR⁸⁰— (wherein R⁶², R⁶³, R⁶⁴, R⁶⁵, R⁶⁶,R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁹ and R⁸⁰each independently represents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl maybe optionally substituted by one or more groups selected from hydroxy,amino, halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy orC₁₋₃alkylsulphanyl) and R⁶¹ is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl which C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionally substitutedwith one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl; (c) R¹ islinked to ring C at a carbon ortho to the position of A-B attachment andis selected from the group consisting of C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkenyloxy, cyano, nitro, halo,trifluoromethylsulphanyl and hydroxy; (d) R¹ is linked to ring C at aring carbon atom ortho to the position of A-B attachment and is selectedfrom the following two groups: 1) —X⁵—R⁸¹ wherein X⁵ is a direct bond,—O—, —S—, —SO—, —SO₂—, —OSO₂—, —SO₂O—, —NR⁸²—, —CO—, —COO—, —OCO—,—CONR⁸³—, —NR⁸⁴CO—, —NR⁸⁵COO—, —SO₂NR⁸⁶—, —NR⁸⁷SO₂—, —CH₂—, —SO₂NR⁸⁸CO—,—OCONR⁸⁹—, -CSNR⁹⁰—, —NR⁹¹CS—, —NR⁹²CSNR⁹³—, —NR⁹⁴CONR⁹⁵—, —CONR⁹⁶SO₂—,—NR⁹⁷CONR⁹⁸SO₂—, —SO₂NR⁹⁹CNNR¹⁰⁰— or —SO₂NR⁹⁹CONR¹⁰⁰— (wherein R⁸², R⁸³,R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹³, R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷,R⁹⁸, R⁹⁹ and R¹⁰⁰ each independently represents hydrogen or C₁₋₄alkylwhich C₁₋₄alkyl may be optionally substituted by one or more groupsselected from hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy,C₁₋₆alkoxy or C₁₋₃alkylsulphanyl) and R⁸¹ is selected from hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl which C₁₋₄alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl is optionally substitutedwith one or more groups selected from hydroxy, amino, halo,C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy and hydroxyC₁₋₆alkyl with theproviso that R¹ is not trifluoromethylsulphanyl, hydroxy, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy or C₂₋₄alkenyloxy; and 2)—X⁶—R¹⁰¹ wherein X⁶ is selected from a direct bond, —CO—, —O—, —OCH₂—,—S—, —SO—, —SO₂— and —NR¹⁰² (wherein R¹⁰² is hydrogen or C₁₋₄alkyl whichC₁₋₄alkyl may be optionally substituted by one or more groups selectedfrom hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy, C₁₋₆alkoxy orC₁₋₃alkylsulphanyl) and R¹⁰¹ is phenyl which is optionally substitutedby 1-4 substituents selected from cyano, nitro,trifluoromethylsulphanyl, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₂₋₆alkenytoxy, halo, hydroxy and amino; n is 1 or 2;(e) either R² and R³ are independently C₁₋₃alkyl optionally substitutedby from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is thenumber of carbon atoms in the said C₁₋₃alkyl, provided that R² and R³are not both methyl;. or R² and R³, together with the carbon atom towhich they are attached, form a 3-5 membered cycloalkyl ring optionallysubstituted by from 1 to 2m−2 fluorine atoms wherein m is the number ofcarbon atoms in said ring; (f) R² and R³ are both methyl or one of R²and R³ is hydrogen or halo and the other is halo or C₁₋₃alkyl optionallysubstituted by from 1 to 2k+l atoms selected from fluoro and chlorowherein k is the number of carbon atoms in the said C₁₋₃alkyl, with theproviso that when either R² or R³ is halo R⁴ is not hydroxy and with theproviso that when either R² or R³ is hydrogen, R⁴is not hydrogen; (g)A-B is selected from —NHCO—, —OCH₂—, —SCH₂—, —NHCH₂—, trans-vinylene,and ethynylene; (h) A-B is —NHCS— or —COCH₂—; (i) R⁴ is hydroxy; (j) R⁴is hydrogen, halo, amino or methyl; but excluding compounds wherein ringC is selected from (a) and R¹ is selected only from (c) and R² and R³are selected from (e) and A-B is selected from (g) and R⁴ is selectedfrom (i); and salts thereof; and pharmaceutically acceptable in vivocleavable prodrugs of said compound of formula (1); and pharmaceuticallyacceptable salts of said compound or said prodrugs; in the manufactureof a medicament for use in the elevation of PDH activity in warm-bloodedanimals such as humans.
 2. The use of a compound of the formula (I) asclaimed in claim 1 wherein R¹ is selected from C₁₋₄alkoxy, halo, nitroor R¹ is X⁵—R⁸¹ wherein X⁵ is a direct bond, —NH—, —NHCO—, —SO—, —SO₂—,—NHSO₂— and R⁸¹ is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or R¹ is—X⁶—R¹⁰¹ wherein —X⁶ is —CO— and R¹⁰¹ is phenyl substituted by halo. 3.The use of a compound of the formula (I) as claimed in claim 1 or 2wherein R¹ is selected from fluoro and chloro.
 4. The use of a compoundof the formula (1) as claimed in claim 1, 2 or 3 wherein R² and R³ areindependently C_(k)alkyl optionally substituted by from 1 to 2k+1 atomsselected from fluoro and chloro wherein k is 1-3, or R² and R³ togetherwith the carbon atom to which they are attached, form a 3-memberedcycloalkyl ring.
 5. The use of a compound of the formula (I) as claimedin claim 1, 2, 3 or 4 wherein one of R² and R³ is methyl and the otheris trifluoromethyl.
 6. The use of a compound of the formula (1) asclaimed in claim 1, 2, 3, 4 or 5 wherein R⁴ is hydroxy, hydrogen ormethyl.
 7. The use of a compound of the formula (1) as claimed in claim1, 2, 3, 4, 5 or 6 wherein R⁴is hydroxy.
 8. The use of a compound of theformula (1) as claimed in claim 1, 2, 3, 4, 5, 6, or 7 wherein n is 1.9. The use of a compound of the formula (I) as claimed in claim 1, 2, 3,4, 5, 6, 7 or 8 wherein ring C is phenyl substituted by one groupselected from P⁴ wherein P⁴ is as defined in claim
 1. 10. The use of acompound of the formula (I) as claimed in claims 1, 2, 3, 4, 5, 6, 7, 8or 9 wherein ring C is phenyl substituted at a position para to A-B by agroup selected from: 1) —X¹—R¹ wherein X¹ is a direct bond, —O—, —S—,—SO—, —SO₂—, —NR⁶— or —CONR⁷— (wherein R⁶ and R⁷ each independentlyrepresents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be optionallysubstituted by one or more groups selected from hydroxy or C₁₋₆alkoxy)and R⁵ is selected from hydrogen and C₁₋₆alkyl, which C₁₋₆alkyl, isoptionally substituted with one or more groups selected from hydroxy,C₁₋₆alkoxy and hydroxyC₁₋₆alkyl with the proviso that —X¹-R⁵ is nothydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; 2) —X¹—C₁₋₄alkyl-X²—R²¹ wherein X¹ isa direct bond, —O—, —S—, —SO—, —SO₂—, —NR⁶— or —CONR⁷— (wherein R⁶ andR⁷ each independently represents hydrogen or C₁₋₄alkyl which C₁₋₄alkylmay be optionally substituted by one or more groups selected fromhydroxy or C₁₋₆alkoxy), X² is a direct bond, —O—, —S—, —SO—, —SO₂—,—NR²²— or —CONR²³— (wherein R²² and R²³each independently representshydrogen or C₁₋₄alkyl which C₁₋₄alkyl may be optionally substituted byone or more groups selected from hydroxy or C₁₋₆alkoxy) and R²¹ ishydrogen or C₁₋₄alkyl, which C,4alkyl is optionally substituted with oneor more groups selected from hydroxy or C₁₋₆alkoxy or R²¹ is R⁴¹ whereinR⁴¹ is as defined in claim 1 with the proviso that —X¹—C₁₋₆alkyl-X²—R²¹is not C₁₋₄alkyl or C₁₋₄alkoxy; 3) —Y²Ar² wherein Y² is X¹ wherein X¹ isa direct bond, —O—, —S—, —SO—, —SO₂—, NR⁶— or —CONR⁷— (wherein R⁶ and R⁷each independently represents hydrogen or C₁₋₄alkyl which C₁₋₄alkyl maybe optionally substituted by one or more groups selected from hydroxy orC₁₋₄alkoxy) and Ar² is as defined in claim
 1. 11. The use of a compoundof the formula (1) as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10wherein A-B is —NHC(O)—.
 12. A compound of formula (I′):

wherein: n is 1 or 2; R^(a) is chloro, fluoro, bromo, nitro or methoxy;R^(b) is C₁₋₆alkyl optionally substituted by one or more groups selectedfrom hydroxy, amino, halo, C₁₋₄alkoxycarbonyl, carboxy or C₁₋₆alkoxy orR^(b) is phenyl, a carbon-linked 6-membered heteroaryl ring containing1-2 nitrogen atoms or a carbon-linked 5-membered heteroaryl ringcontaining 1-3 heteroatoms selected independently from O, N and S,wherein said phenyl or heteroaryl ring is substituted by one or moregroups selected from i)-iii) and is optionally further substituted witha group selected from iv): i) —X^(a)—R^(c) wherein X^(a) is a directbond, —O—, —S—, —SO—, —SO₂—, —NR^(d)— or —CONR^(e)— (wherein R^(d) andR^(e) each independently represents hydrogen or C₁₋₄alkyl whichC₁₋₄alkyl is optionally substituted with one or more groups selectedfrom hydroxy or C₁₋₄alkoxy) and R^(c) is selected from hydrogen orC₁₋₆alkyl which C₁₋₆alkyl is optionally substituted with one or morehydroxy or C₁₋₄alkoxy with the proviso that 'X^(a)—R^(c) is notC₁₋₄alkyl or C₁₋₄alkoxy; ii) a 4-12 membered heterocyclic moietycontaining 1-4 heteroatoms selected independently from O, N and S whichheterocyclic moiety may be aromatic or non-aromatic and is optionallysubstituted with one or more groups selected from hydroxy, halo,C₁₋₄alkoxy, C₁₋₄alkyl or cyano; iii) —X^(a)—C₁₋₆alkyl-X^(b)—R^(c)wherein X^(a) and R^(c) are as defined hereinbefore and X^(b) is —S—,—SO— or —SO₂—; iv) cyano, hydroxy, halo, C₁₋₄alkoxy, C₁₋₄alkyl; and andsalts thereof; and pharmaceutically acceptable in vivo cleavableprodrugs of said compound of formula (1); and pharmaceuticallyacceptable salts of said compound or said prodrugs.
 13. A compound offormula (I′) as claimed in claim 12 wherein R^(a) is chloro or fluoro.14. A compound of formula (I′) as claimed in claim 12 or 13 whereinR^(b) is C₁₋₄alkyl optionally substituted by hydroxy or R^(b) is phenylwherein said phenyl is substituted by one group selected from i)-iii):i) —X^(a)—R^(c) wherein X^(a) is —SO—, —SO₂—, —NR^(d)— or —CONR^(e)—(wherein R^(d) and R^(c) each independently represents hydrogen orC₁₋₄alkyl) and R^(c) is selected from hydrogen or C₁₋₆alkyl whichC₁₋₆alkyl is optionally substituted with one or more hydroxy; ii) a 4-12membered heterocyclic moiety containing 1-4 heteroatoms selectedindependently from O, N and S which heterocyclic moiety may be aromaticor non-aromatic; iii) —X^(a)—C₁₋₆alkyl-X^(b)—R^(c) wherein X^(a) andR^(c) are as defined hereinbefore and X^(b) is —S—.
 15. A compound offormula (I′) as claimed in claim 12, 13 or 14 which is selected from:(R)-N-[2-Chloro4-(4-mesylphenylsulphinyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-{2-Chloro-4-[4-(2-oxo-pyrrolidin-1-yl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-{2-Fluoro4-[4-(2-hydroxyethylamino)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-{2-Chloro4-[4-(2-hydroxyethylamino)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-{2-Chloro-4-[4-(2-methylsulphanylethylamino)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-{2-Chloro-4-[4-(methylsulphinyl)phenylsulphinyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-[2-Chloro-4-(2-hydroxyethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-(2-Chloro-4-ethylsulphonylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-{2-Chloro-4-[4-(N,N-dimethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;(R)-N-[2-Chloro-4-(4-aminophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;and salts thereof; and pharmaceutically acceptable in vivo cleavableprodrugs of said compound of formula (I); and pharmaceuticallyacceptable salts of said compound or said prodrugs.
 16. A pharmaceuticalcomposition which comprises a compound of the formula (I′) as claimed inclaim 12, 13, 14 or 15 or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable excipient or carrier. 17.A process for preparing a compound of formula (I′) as claimed in claim12, 13, 14 or 15 or a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof, which process (in which variable groups areas defined for formula (I′) unless otherwise stated) comprises of: (a)deprotecting a protected compound of formula (II′):

where Pg is an alcohol protecting group; (b) oxidising a compound offormula (VI′)

(c) coupling a compound of formula (VII′):

wherein J is NH₂, with an acid of formula (VII′)

wherein X is OH; (d) coupling an aniline of formula (VII′) wherein J is—NH₂ with an activated acid derivative of formula (VIII′); (e) reactinga compound of formula (IX′):

with a base to yield the dianion, followed by treatment of the dianionwith oxygen in the presence of a reducing agent; or by treatment with aperoxyacid; (f) reacting a compound of formula (XII′):

with a compound of formula R^(y)M wherein M is an alkali metal or aGrignard compound of formula R^(y)MgBr or R^(y)MgCl wherein one of R^(x)and R^(y) is CF₃ and the other is Me; and thereafter if necessary: i)converting a compound of the formula (I′) into another compound of theformula (I′); ii) removing any protecting groups; or iii) forming apharmaceutically acceptable salt or in vivo hydrolysable ester.